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CitationGPTRetr300

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Regional Aβ-tau interactions promote onset and acceleration of Alzheimer's disease tau spreading. Abstract of the paper: Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer's disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject to remote, connectivity-mediated amyloid-beta/tau interactions linked to initial tau spreading. Second, we identify the inferior temporal gyrus as the region featuring the greatest local amyloid-beta/tau interactions and a connectivity profile well suited to accelerate tau propagation. Taken together, our data address long-standing questions regarding the topographical dissimilarity between early amyloid-beta and tau deposition.

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CitationGPTRetr301

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer's disease. Abstract of the paper: The links between β-amyloid (Aβ) and tau in Alzheimer's disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aβ pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aβ aggregation started. These results show that Aβ pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.

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CitationGPTRetr302

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Imaging the evolution and pathophysiology of Alzheimer disease. Abstract of the paper: Technologies for imaging the pathophysiology of Alzheimer disease (AD) now permit studies of the relationships between the two major proteins deposited in this disease - amyloid-β (Aβ) and tau - and their effects on measures of neurodegeneration and cognition in humans. Deposition of Aβ in the medial parietal cortex appears to be the first stage in the development of AD, although tau aggregates in the medial temporal lobe (MTL) precede Aβ deposition in cognitively healthy older people. Whether aggregation of tau in the MTL is the first stage in AD or a fairly benign phenomenon that may be transformed and spread in the presence of Aβ is a major unresolved question. Despite a strong link between Aβ and tau, the relationship between Aβ and neurodegeneration is weak; rather, it is tau that is associated with brain atrophy and hypometabolism, which, in turn, are related to cognition. Although there is support for an interaction between Aβ and tau resulting in neurodegeneration that leads to dementia, the unknown nature of this interaction, the strikingly different patterns of brain Aβ and tau deposition and the appearance of neurodegeneration in the absence of Aβ and tau are challenges to this model that ultimately must be explained.

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CitationGPTRetr303

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Tau pathogenesis is promoted by Aβ1-42 but not Aβ1-40. Abstract of the paper: BACKGROUND The relationship between the pathogenic amyloid β-peptide species Aβ1-42 and tau pathology has been well studied and suggests that Aβ1-42 can accelerate tau pathology in vitro and in vivo. The manners if any in which Aβ1-40 interacts with tau remains poorly understood. In order to answer this question, we used cell-based system, transgenic fly and transgenic mice as models to study the interaction between Aβ1-42 and Aβ1-40. RESULTS In our established cellular model, live cell imaging (using confocal microscopy) combined with biochemical data showed that exposure to Aβ1-42 induced cleavage, phosphorylation and aggregation of wild-type/full length tau while exposure to Aβ1-40 didn't. Functional studies with Aβ1-40 were carried out in tau-GFP transgenic flies and showed that Aβ1-42, as previously reported, disrupted cytoskeletal structure while Aβ1-40 had no effect at same dose. To further explore how Aβ1-40 affects tau pathology in vivo, P301S mice (tau transgenic mice) were injected intracerebrally with either Aβ1-42 or Aβ1-40. We found that treatment with Aβ1-42 induced tau phosphorylation, cleavage and aggregation of tau in P301S mice. By contrast, Aβ1-40 injection didn't alter total tau, phospho-tau (recognized by PHF-1) or cleavage of tau, but interestingly, phosphorylation at Ser262 was shown to be significantly decreased after direct inject of Aβ1-40 into the entorhinal cortex of P301S mice. CONCLUSIONS These results demonstrate that Aβ1-40 plays different role in tau pathogenesis compared to Aβ1-42. Aβ1-40 may have a protective role in tau pathogenesis by reducing phosphorylation at Ser262, which has been shown to be neurotoxic.

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CitationGPTRetr304

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Abstract of the paper: Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque-bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs). These distinct tau pathologies have different temporal onsets and functional consequences on neural activity and behavior. Notably, we found that Aβ plaques created a unique environment that facilitated the rapid amplification of proteopathic AD-tau seeds into large tau aggregates, initially appearing as NP tau, which was followed by the formation and spread of NFTs and NTs, likely through secondary seeding events. Our study provides insights into a new multistep mechanism underlying Aβ plaque-associated tau pathogenesis.

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CitationGPTRetr305

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Comparison of Amyloid β and Tau Spread Models in Alzheimer's Disease. Abstract of the paper: Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer's disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models' performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD.

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CitationGPTRetr306

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer's Disease. Abstract of the paper: Alzheimer's disease (AD) is pathologically defined by extracellular accumulation of amyloid-β (Aβ) peptides generated by the cleavage of amyloid precursor protein (APP), strings of hyperphosphorylated Tau proteins accumulating inside neurons known as neurofibrillary tangles (NFTs) and neuronal loss. The association between the two hallmarks and cognitive decline has been known since the beginning of the 20th century when the first description of the disease was carried out by Alois Alzheimer. Today, more than 40 million people worldwide are affected by AD that represents the most common cause of dementia and there is still no effective treatment available to cure the disease. In general, the aggregation of Aβ is considered an essential trigger in AD pathogenesis that gives rise to NFTs, neuronal dysfunction and dementia. During the process leading to AD, tau and Aβ first misfold and form aggregates in one brain region, from where they spread to interconnected areas of the brain thereby inducing its gradual morphological and functional deterioration. In this mini-review article, we present an overview of the current literature on the spreading mechanisms of Aβ and tau pathology in AD since a more profound understanding is necessary to design therapeutic approaches aimed at preventing or halting disease progression.

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CitationGPTRetr307

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Filling the gaps in the abeta cascade hypothesis of Alzheimer's disease. Abstract of the paper: Advances in the understanding of Alzheimer's disease (AD) pathogenesis provide strong support for a modified version of the amyloid cascade hypothesis, which is now often referred to as the amyloid beta protein (Abeta) cascade hypothesis. The basic tenant of this modified hypothesis is that Abeta aggregates trigger a complex pathological cascade leading to neurodegeneration. Thus, as opposed to the original amyloid hypothesis, whose basic tenant was that amyloid deposits cause AD, the Abeta hypothesis is more inclusive in that it takes into account the possibility that several different Abeta assemblies might contribute to AD pathogenesis and not merely the detectable amyloid deposits within the brain. Significantly, the Abeta hypothesis has provided the rationale for a plethora of therapeutic interventions that target Abeta production, aggregation or clearance. Indeed, AD research is entering an exciting phase in which strategies derived from basic research will be tested in humans. Despite this progress, many aspects of AD pathogenesis, particularly those downstream of Abeta accumulation are not well understood. Herein, we explore several observations that serve to illustrate the more enigmatic aspects of the Abeta hypothesis, and discuss why further basic research may be critical in order to develop therapies designed to halt neurodegeneration and reverse cognitive decline in patients already suffering from AD dementia.

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CitationGPTRetr308

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Dysfunctional microglia and tau pathology in Alzheimer's disease. Abstract of the paper: Extensive human studies and animal models show that chronic immune system stimulation involving microglia, inflammasome, complement activation, synthesis of cytokines, and reactive oxygen species exacerbates neurodegeneration in Alzheimer's disease (AD) and other tauopathies. Abnormalities in tau, Aβ, and microglial activation are frequently observed in dementia patients and indicate that these elements may work in concert to cause cognitive impairment. Contradicting reports from postmortem studies demonstrating the presence of Aβ aggregates in the brains of cognitively healthy individuals, as well as other investigations, show that tau aggregation is more strongly associated with synapse loss, neurodegeneration, and cognitive decline than amyloid pathology. Tau association with microtubules' surface promotes their growth and maintains their assembly, dynamicity, and stability. In contrast, the reduced affinity of hyperphosphorylated and mislocalized tau to microtubules leads to axonal deficits and neurofibrillary tangles (NFTs). Loss of microglial neuroprotective and phagocytic functions, as indicated by the faulty clearance of amyloid plaques, as well as correlations between microglial activation and tau tangle spread, all demonstrate the critical involvement of malfunctioning microglia in driving tau propagation. This review discusses the recent reports on the contribution of microglial cells to the development and progression of tau pathology. The detailed study of pathogenic mechanisms involved in interactions between neuroinflammation and tau spread is critical in identifying the targets for efficacious treatment strategies in AD.

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CitationGPTRetr309

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Abstract of the paper: Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer's disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and Aβ propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as 'axon related' and the Aβ profile as 'dendrite related'. This study reveals distinct genetic profiles that may confer vulnerability to tau and Aβ in vivo propagation in the human brain.

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CitationGPTRetr310

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Human secreted tau increases amyloid-beta production. Abstract of the paper: The interaction of amyloid-beta (Aβ) and tau in the pathogenesis of Alzheimer's disease is a subject of intense inquiry, with the bulk of evidence indicating that changes in tau are downstream of Aβ. It has been shown however, that human tau overexpression in amyloid precursor protein transgenic mice increases Aβ plaque deposition. Here, we confirm that human tau increases Aβ levels. To determine if the observed changes in Aβ levels were because of intracellular or extracellular secreted tau (eTau for extracellular tau), we affinity purified secreted tau from Alzheimer's disease patient-derived cortical neuron conditioned media and analyzed it by liquid chromatography-mass spectrometry. We found the extracellular species to be composed predominantly of a series of N-terminal fragments of tau, with no evidence of C-terminal tau fragments. We characterized a subset of high affinity tau antibodies, each capable of engaging and neutralizing eTau. We found that neutralizing eTau reduces Aβ levels in vitro in primary human cortical neurons where exogenously adding eTau increases Aβ levels. In vivo, neutralizing human tau in 2 human tau transgenic models also reduced Aβ levels. We show that the human tau insert sequence is sufficient to cause the observed increase in Aβ levels. Our data furthermore suggest that neuronal hyperactivity may be the mechanism by which this regulation occurs. We show that neuronal hyperactivity regulates both eTau secretion and Aβ production. Electrophysiological analysis shows for the first time that secreted eTau causes neuronal hyperactivity. Its induction of hyperactivity may be the mechanism by which eTau regulates Aβ production. Together with previous findings, these data posit a novel connection between tau and Aβ, suggesting a dynamic mechanism of positive feed forward regulation. Aβ drives the disease pathway through tau, with eTau further increasing Aβ levels, perpetuating a destructive cycle.

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CitationGPTRetr311

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: A Unifying Hypothesis for Alzheimer's Disease: From Plaques to Neurodegeneration. Abstract of the paper: Evidence suggests that amyloid β is highly toxic to synapses in a phospho-Tau-dependent manner. Here, I present a hypothesis that links previous evidence from the first rise of amyloid β through to Tau tangles and neurodegeneration. In the immediate vicinity of plaques, concentrated soluble amyloid β occurs in equilibrium with deposited forms. Initially, plaques cover only a small percentage of brain volume. Microglia, by efficiently removing damaged synapses, may prevent spread of damage along the axon, restricting damage to the immediate vicinity of plaques. However, as plaque load increases, as seen in Alzheimer's disease, an individual axon may suffer multiple points of damage, leading to dissociation of Tau, formation of a tangle, and loss of the axon. As more axons suffer this fate, the network eventually degenerates. According to this hypothesis, the degree of plaque load that an individual can tolerate would depend on the efficiency of their microglia in removing amyloid-β-damaged synapses and the distribution of plaques, relative to axon trajectories, would determine the eventual cognitive symptoms.

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CitationGPTRetr312

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Intercellular transfer of tau aggregates and spreading of tau pathology: Implications for therapeutic strategies. Abstract of the paper: Filaments made of hyperphosphorylated tau protein are encountered in a group of neurodegenerative disorders termed tauopathies. The most prevalent tauopathy, Alzheimer's disease (AD), additionally presents with extracellular deposits of the amyloid-β peptide (Aβ). Current symptomatic treatments have shown short term benefits in reducing cognitive symptoms as well as behavioral abnormalities in patients with mild to moderate AD but there is still no effective treatment to prevent or reverse AD. For decades, the amyloid cascade hypothesis of AD dominated basic research and focused pharmaceutical interest on Aβ. However, the existence of tauopathies that are devoid of Aβ deposits, together with the discovery of mutations in the tau gene leading to frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17T), confirmed the importance of tau per se in disease. Tau became an interesting disease target in its own right. We will review here recent research on cell-to-cell propagation of tau pathology, which we believe to be central to disease progression, and discuss tau immunotherapy in the light of these findings. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

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CitationGPTRetr313

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease. Abstract of the paper: Extracellular neuritic plaques composed of amyloid‑β (Aβ) protein and intracellular neurofibrillary tangles containing phosphorylated tau protein are the two hallmark proteins of Alzheimer's disease (AD), and the separate neurotoxicity of these proteins in AD has been extensively studied. However, interventions that target Aβ or tau individually have not yielded substantial breakthroughs. The interest in the interactions between Aβ and tau in AD is increasing, but related drug investigations are in their infancy. This review discusses how Aβ accelerates tau phosphorylation and the possible mechanisms and pathways by which tau mediates Aβ toxicity. This review also describes the possible synergistic effects between Aβ and tau on microglial cells and astrocytes. Studies suggest that the coexistence of Aβ plaques and phosphorylated tau is related to the mechanism by which Aβ facilitates the propagation of tau aggregation in neuritic plaques. The interactions between Aβ and tau mediate cognitive dysfunction in patients with AD. In summary, this review summarizes recent data on the interplay between Aβ and tau to promote a better understanding of the roles of these proteins in the pathological process of AD and provide new insights into interventions against AD.

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CitationGPTRetr314

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein. Abstract of the paper: Extracellular deposition of amyloid β-protein (Aβ) in amyloid plaques and intracellular accumulation of abnormally phosphorylated τ-protein (p-τ) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer's disease (AD). Both lesions develop in parallel in the human brain throughout the preclinical and clinical course of AD. Nevertheless, it is not yet clear whether there is a direct link between Aβ and τ pathology or whether other proteins are involved in this process. To address this question, we crossed amyloid precursor protein (APP) transgenic mice overexpressing human APP with the Swedish mutation (670/671 KM → NL) (APP23), human wild-type APP (APP51/16), or a proenkephalin signal peptide linked to human Aβ42 (APP48) with τ-transgenic mice overexpressing human mutant 4-repeat τ-protein with the P301S mutation (TAU58). In 6-month-old APP23xTAU58 and APP51/16xTAU58 mice, soluble Aβ was associated with the aggravation of p-τ pathology propagation into the CA1/subiculum region, whereas 6-month-old TAU58 and APP48xTAU58 mice neither exhibited significant amounts of p-τ pathology in the CA1/subiculum region nor displayed significant levels of soluble Aβ in the forebrain. In APP23xTAU58 and APP51/16xTAU58 mice showing an acceleration of p-τ propagation, Aβ and p-τ were co-immunoprecipitated with cellular prion protein (PrPC). A similar interaction between PrPC, p-τ and Aβ was observed in human AD brains. This association was particularly noticed in 60% of the symptomatic AD cases in our sample, suggesting that PrPC may play a role in the progression of AD pathology. An in vitro pull-down assay confirmed that PrPC is capable of interacting with Aβ and p-τ. Using a proximity ligation assay, we could demonstrate proximity (less than ~ 30-40 nm distance) between PrPC and Aβ and between PrPC and p-τ in APP23xTAU58 mouse brain as well as in human AD brain. Proximity between PrPC and p-τ was also seen in APP51/16xTAU58, APP48xTAU58, and TAU58 mice. Based on these findings, it is tempting to speculate that PrPC is a critical player in the interplay between Aβ and p-τ propagation at least in a large group of AD cases. Preexisting p-τ pathology interacting with PrPC, thereby, appears to be a prerequisite for Aβ to function as a p-τ pathology accelerator via PrPC.

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CitationGPTRetr315

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau. Abstract of the paper: Alzheimer's disease (AD) is characterized by extracellular amyloid β (Aβ) deposition and intracellular tau aggregation. Many studies have indicated some association between these processes, but it remains unknown how the two pathologies are linked. In this study, we investigated whether expression of amyloid precursor protein (APP) influences extracellular seed-dependent intracellular tau accumulation in cultured cells. Treatment of tau-expressing SH-SY5Y cells with Aβ fibrils did not induce intracellular tau aggregation. On the other hand, in cells expressing both tau and APP, treatment with tau fibrils or Sarkosyl-insoluble tau from AD brains induced intracellular tau aggregation. The seed-dependent intracellular tau aggregation was not induced by expression of APP lacking the extracellular domain. The amount of phosphorylated tau aggregates in cultured cells was dose dependently elevated in response to increased levels of APP on the cell membrane. Our results indicate that the extracellular region of APP is involved in uptake of tau fibrils into cells, raising the possibility that APP, but not Aβ, influences cell-to-cell spreading of tau pathologies in AD by serving as a receptor of abnormal tau aggregates.

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CitationGPTRetr316

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Synergy between amyloid-β and tau in Alzheimer's disease. Abstract of the paper: Patients with Alzheimer's disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. For many years, the prevailing view of AD pathogenesis has been that changes in Aβ precipitate the disease process and initiate a deleterious cascade involving tau pathology and neurodegeneration. Beyond this 'triggering' function, it has been typically presumed that Aβ and tau act independently and in the absence of specific interaction. However, accumulating evidence now suggests otherwise and contends that both pathologies have synergistic effects. This could not only help explain negative results from anti-Aβ clinical trials but also suggest that trials directed solely at tau may need to be reconsidered. Here, drawing from extensive human and disease model data, we highlight the latest evidence base pertaining to the complex Aβ-tau interaction and underscore its crucial importance to elucidating disease pathogenesis and the design of next-generation AD therapeutic trials.

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CitationGPTRetr317

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Amyloid β accelerates phosphorylation of tau and neurofibrillary tangle formation in an amyloid precursor protein and tau double-transgenic mouse model. Abstract of the paper: In Alzheimer's disease, Aβ deposits are considered the initial cardinal events that induce tauopathy secondarily. However, the relationship between Aβ amyloidosis and tauopathy has not been determined in detail. We produced double transgenic mice, 2×TgTau(+/-) APP(+/-) , by mating Tg2576 mice that exhibit Aβ amyloidosis and TgTauP301L mice that show tauopathy, and statistically analyzed the effect of Aβ accumulation on tauopathy. There was no significant difference in theprogression of Aβ accumulation among 2×TgTau(+/-) APP(+/-) and 1×TgTau(-/-) APP(+/-) , and tau accumulation among 2×TgTau(+/-) APP(+/-) and 1×Tg Tau(+/-) APP(-/-) . The appearance rates of phosphorylated tau developing in neurons and processes were significantly accelerated in 2×TgTau(+/-) APP(+/-) mice compared with those in 1×TgTau(+/-) APP(-/-) mice at 23 months of age. Accumulation of phosphorylated and confomationally altered tau and GSK3β in neuronal processes was accelerated in the white matter in 2×TgTau(+/-) APP(+/-) . The level of phosphorylated tau in the sarkosyl-insoluble fraction was increased in 2×TgTau(+/-) APP(+/-) brains compared with that in 1×TgTau(+/-) APP(-/-) brains. Thus, Aβ amyloid partially enhances tauopathy through accumulation of insoluble, phosphorylated, and conformationally changed tau in neuronal cytoplasm and processes in the late stage.

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CitationGPTRetr318

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: The Interplay of Tau Protein and β-Amyloid: While Tauopathy Spreads More Profoundly Than Amyloidopathy, Both Processes Are Almost Equally Pathogenic. Abstract of the paper: Alzheimer's disease (AD) is a neurodegenerative disorder, in which amyloid precursor protein (APP) misprocessing and tau protein hyperphosphorylation are well-established pathogenic cascades. Despite extensive considerations, the central mediator of neuronal cell death upon AD remains under debate. Therefore, we examined the direct interplay between tauopathy and amyloidopathy processes. We employed primary culture neurons and examined pathogenic P-tau and Aβ oligomers upon hypoxia treatment by immunofluorescence and immunoblotting. We observed both tauopathy and amyloidopathy processes upon the hypoxia condition. We also applied Aβ1-42 or P-tau onto primary cultured neurons. We overexpressed P-tau in SH-SY5Y cells and found Aβ accumulation. Furthermore, adult male rats received Aβ1-42 or pathogenic P-tau in the dorsal hippocampus and were examined for 8 weeks. Learning and memory performance, as well as anxiety behaviors, were assessed by Morris water maze and elevated plus-maze tests. Both Aβ1-42 and pathogenic P-tau significantly induced learning and memory deficits and enhanced anxiety behavior after treatment 2 weeks. Aβ administration induced robust tauopathy distribution in the cortex, striatum, and corpus callosum as well as CA1. On the other hand, P-tau treatment developed Aβ oligomers in the cortex and CA1 only. Our findings indicate that Aβ1-42 and pathogenic P-tau may induce each other and cause almost identical neurotoxicity in a time-dependent manner, while tauopathy seems to be more distributable than amyloidopathy.

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CitationGPTRetr319

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the idea that aβ deposition acts as a driving force for tau pathogenesis by fostering neurogenesis and supporting migration is consistent with several findings showing that aβ deposition facilitates both the pathogenicity 502506 and spread 335 507 508 of tau in the brain even when aβ and tau are not topographically closely related Title of the paper: Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade. Abstract of the paper: The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Association of Antioxidant Vitamins A, C, E and Carotenoids with Cognitive Performance over Time: A Cohort Study of Middle-Aged Adults. Abstract of the paper: Carotenoids may strengthen the association of antioxidant vitamins A, C, and E with favorable cognitive outcomes over time, though a few prospective studies have examined this hypothesis. We evaluated the longitudinal data from 1251 participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (Age at visit 1 in 2004-2009 (v1): 30-65 years). Vitamins A, C, and E dietary intakes and total and individual dietary carotenoids were computed using two 24-h recalls at v1. Cognitive tests, covering global mental status and domains of memory/learning, attention, psychomotor speed, visuo-spatial, language/verbal, and executive function were conducted at v1 and/or v2 (2009-2013); mean ± SD follow-up: 4.66 ± 0.93 years. Mixed-effects linear regression models detected an interaction between vitamin E and total (and individual) carotenoids for three of 11 cognitive tests at v1, with only one meeting the statistical significance upon multiple testing correction whereby vitamin E was linked with greater verbal memory performance in the uppermost total carotenoid tertile (γ0 = +0.26 ± 0.08, p = 0.002), a synergism largely driven by carotenoid lycopene. Vitamins A and C showed no consistent interactions with carotenoids. In conclusion, we provide partial evidence for synergism between vitamin E and carotenoids in relation to better baseline cognitive performance, pending further studies with time-dependent exposures and randomized trials directly examining this synergism.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Lycopene and cognitive function. Abstract of the paper: Decreases in cognitive function related to increases in oxidative stress and inflammation occur with ageing. Acknowledging the free radical-quenching activity and anti-inflammatory action of the carotenoid lycopene, the aim of the present review was to assess if there is evidence for a protective relationship between lycopene and maintained cognitive function or between lycopene and development or progression of dementia. A systematic literature search identified five cross-sectional and five longitudinal studies examining these outcomes in relation to circulating or dietary lycopene. Among four studies evaluating relationships between lycopene and maintained cognition, three reported significant positive relationships. Neither of the two studies reporting on relationship between lycopene and development of dementia reported significant results. Of four studies investigating circulating lycopene and pre-existing dementia, only one reported significant associations between lower circulating lycopene and higher rates of Alzheimer's disease mortality. Acknowledging heterogeneity among studies, there is insufficient evidence and a paucity of data to draw firm conclusions or tease apart direct effects of lycopene. Nevertheless, as low circulating lycopene is a predictor of all-cause mortality, further investigation into its relationship with cognitive longevity and dementia-related mortality is warranted.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Plasma carotenoid levels and cognitive performance in an elderly population: results of the EVA Study. Abstract of the paper: BACKGROUND The hypothesis of carotenoids having a preventive role in cognitive impairment is suggested by their antioxidant properties. METHODS We examined, in a cross-sectional analysis, the relationship between cognitive performance (assessed by the Mini-Mental State Examination, Trail Making Test Part B, Digit Symbol Substitution, Finger Tapping Test, and Word Fluency Test) and different plasma carotenoids (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, and trans-beta-carotene and cis-beta-carotene) in a healthy elderly population (the EVA,"Etude du Vieillissement Artériel," study; n = 589, age = 73.5 +/- 3 years). RESULTS Logistic regression showed that participants with the lowest cognitive functioning (<25th percentile) had a higher probability of having low levels of specific plasma carotenoids (<1st quartile): lycopene and zeaxanthin. For zeaxanthin, odds ratios (ORs) were as follows: OR(DSS) = 1.97 (95% confidence interval [CI] = 1.21-3.20), OR(FTT) = 1.70 (CI = 1.05-2.74), and OR(WFT) = 1.82 (CI = 1.08-3.07); for lycopene, OR(DSS) = 1.93 (CI = 1.20-3.12) and OR(TMTB) = 1.64 (CI = 1.04-2.59). CONCLUSION Even if it is not possible to affirm if these low levels of carotenoids precede or are the consequence of cognitive impairment, our results suggest that low carotenoid levels could play a role in cognitive impairment. The biological significance of our findings needs further research.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Plasma concentrations of vitamins A and E and carotenoids in Alzheimer's disease. Abstract of the paper: In a case/control study, serum concentrations of vitamins A and E and major carotenoids were determined in patients with Alzheimer's disease, multi-infarct dementia and control subjects. The results showed that both Alzheimer's and multi-infarct dementia patients had significantly lower levels of vitamin E and beta-carotene than controls (vitamin E: 18.65 +/- 3.62 mumol/l in Alzheimer's disease and 15.80 +/- 6.93 mumol/l in multi-infarct dementia versus 30.03 +/- 12.03 mumol/l in controls; beta-carotene less than 0.13 to 0.42 mumol/l in Alzheimer's disease and less than 0.13 to 0.30 mumol/l in multi-infarct dementia versus 0.13 to 1.53 mumol/l in controls). Vitamin A was significantly reduced only in the Alzheimer's patients (1.56 +/- 0.78 mumol/l in Alzheimer's disease versus 2.13 +/- 0.86 mumol/l in controls).

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Serum lycopene, lutein and zeaxanthin, and the risk of Alzheimer's disease mortality in older adults. Abstract of the paper: BACKGROUND Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD). Accumulating evidence shows that antioxidant-rich food reduces the risk of AD by inhibiting oxidative stress. This study investigates whether serum levels of carotenoids were associated with the risk of AD mortality in a nationally representative sample of US adults. METHODS We used data from the Third Nutrition and Health Examination Survey (NHANES III) database and the NHANES III Linked Mortality File. A total of 6,958 participants aged older than 50 years were included in this study. RESULTS We found that high serum levels of lycopene and lutein+zeaxanthin at baseline were associated with a lower risk of AD mortality after adjustment for potential covariates. The reduction in the mortality risk was progressively raised by increasing serum lycopene (HR = 0.26, 95% CI 0.10-0.69) and lutein+zeaxanthin (HR = 0.43, 95% CI 0.22-0.85) levels. In contrast, no associations with AD mortality were observed for other serum carotenoids, including alpha-carotene, beta-carotene, and beta-cryptoxanthin. CONCLUSION High serum levels of lycopene and lutein+zeaxanthin are associated with a lower risk of AD mortality in adults. Our findings suggest that a high intake of lycopene- or lutein+zeaxanthin-rich food may be important for reducing the AD mortality risk.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Carotenoids and human health. Abstract of the paper: Oxidative stress is an important contributor to the risk of chronic diseases. Dietary guidelines recommend increased consumption of fruits and vegetables to combat the incidence of human diseases such as cancer, cardiovascular disease, osteoporosis and diabetes. Fruits and vegetables are good sources of antioxidant phytochemicals that mitigate the damaging effect of oxidative stress. Carotenoids are a group of phytochemicals that are responsible for different colors of the foods. They are recognized as playing an important role in the prevention of human diseases and maintaining good health. In addition to being potent antioxidants some carotenoids also contribute to dietary vitamin A. There is scientific evidence in support of the beneficial role of phytochemicals in the prevention of several chronic diseases. Although the chemistry of carotenoids has been studied extensively, their bioavailability, metabolism and biological functions are only now beginning to be investigated. Recent interest in carotenoids has focused on the role of lycopene in human health. Unlike some other carotenoids, lycopene does not have pro-vitamin A properties. Because of the unsaturated nature of lycopene it is considered to be a potent antioxidant and a singlet oxygen quencher. This article will review carotenoids in general and lycopene in particular for their role in human health.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Relationship between Serum and Brain Carotenoids, α-Tocopherol, and Retinol Concentrations and Cognitive Performance in the Oldest Old from the Georgia Centenarian Study. Abstract of the paper: Oxidative stress is involved in age-related cognitive decline. The dietary antioxidants, carotenoids, tocopherols, and vitamin A may play a role in the prevention or delay in cognitive decline. In this study, sera were obtained from 78 octogenarians and 220 centenarians from the Georgia Centenarian Study. Brain tissues were obtained from 47 centenarian decedents. Samples were analyzed for carotenoids, α-tocopherol, and retinol using HPLC. Analyte concentrations were compared with cognitive tests designed to evaluate global cognition, dementia, depression and cognitive domains (memory, processing speed, attention, and executive functioning). Serum lutein, zeaxanthin, and β-carotene concentrations were most consistently related to better cognition (P < 0.05) in the whole population and in the centenarians. Only serum lutein was significantly related to better cognition in the octogenarians. In brain, lutein and β-carotene were related to cognition with lutein being consistently associated with a range of measures. There were fewer significant relationships for α-tocopherol and a negative relationship between brain retinol concentrations and delayed recognition. These findings suggest that the status of certain carotenoids in the old may reflect their cognitive function. The protective effect may not be related to an antioxidant effect given that α-tocopherol was less related to cognition than these carotenoids.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Serum levels of beta-carotene, alpha-carotene and vitamin A in patients with Alzheimer's disease. Abstract of the paper: To elucidate the possible role of carotenoids and vitamin A as risk factors for Alzheimer's disease (AD), we compared serum levels of beta-carotene and alpha-carotene, and vitamin A, measured by isocratic high performance liquid chromatography, of 38 AD patients and 42 controls. The serum levels of alpha-carotene did not differ significantly between AD patients and control groups. However, the serum levels of beta-carotene and vitamin A were significantly lower in the AD-patient group. These values did not correlate to age, age at onset or score on the MiniMental State Examination. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that low serum beta-carotene concentrations in AD patients could be related to a deficiency in dietary intake of this provitamin, although its possible relationship with risk for AD could not be excluded.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Plasma Antioxidant Status in Patients with Alzheimer's Disease and Cognitively Intact Elderly: A Meta-Analysis of Case-Control Studies. Abstract of the paper: Serum antioxidants may afford neuroprotection against Alzheimer's disease (AD) via correction of the pro-oxidative imbalance but findings reported have been inconsistent. We compared the pooled mean difference in serum levels of ten dietary antioxidants between patients with AD and cognitively intact controls from 52 studies in meta-analyses using random-effects models. Patients with AD had significantly lower plasma levels of α-carotene, β-carotene, lycopene, lutein, vitamin A, C, and E, and uric acid. No significant difference was observed for plasma levels of β-cryptoxanthin and zeaxanthin. Considerable heterogeneity was detected across studies. The lower serum levels of dietary antioxidants from the carotene and vitamin subclasses observed in individuals with AD suggest reduced systemic availability of these subclasses in this prevalent form of dementia. To our knowledge, these are the first meta-analyses to demonstrate lower serum lycopene and to evaluate β-cryptoxanthin, lutein, and zeaxanthin levels in AD. In light of the significant heterogeneity detected across studies, caution should be exercised in the interpretation of the data and therapeutic intervention approaches considered through supplementation measures. Our data may better inform interventions to improve antioxidant status in a condition of major public health importance.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Vitamins in aging, health, and longevity. Abstract of the paper: Evidence of epidemiological associations of vitamins and disease states have been found for nine vitamins. In observational studies, people with a high intake of antioxidant vitamins by regular diet or as food supplements generally have a lower risk of major chronic disease, such as myocardial infarction or stroke, than people who are low consumers of antioxidant vitamins. Prospectively, folate appears to reduce the incidence of neural tube defects. Vitamin D is associated with a decreased occurrence of fractures when taken with calcium. Zinc, betacarotene, and vitamin E appear to slow the progression of macular degeneration, but do not reduce the incidence. Vitamin E and lycopene may decrease the risk of prostate cancer. In other randomized controlled trials, the apparent beneficial results of a high intake of antioxidant vitamins seen in observational studies have not been confirmed. There is increasing concern from these trials that pharmacological supplementation of vitamins may be associated with a higher mortality risk.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Beta-carotene and other carotenoids as antioxidants. Abstract of the paper: Carotenoids are natural pigments which are synthesized by plants and are responsible for the bright colors of various fruits and vegetables. There are several dozen carotenoids in the foods that we eat, and most of these carotenoids have antioxidant activity. Beta-carotene has been best studied since, in most countries it is the most common carotenoid in fruits and vegetables. However, in the U.S., lycopene from tomatoes now is consumed in approximately the same amount as beta-carotene. Antioxidants (including carotenoids) have been studied for their ability to prevent chronic disease. Beta-carotene and others carotenoids have antioxidant properties in vitro and in animal models. Mixtures of carotenoids or associations with others antioxidants (e.g. vitamin E) can increase their activity against free radicals. The use of animals models for studying carotenoids is limited since most of the animals do not absorb or metabolize carotenoids similarly to humans. Epidemiologic studies have shown an inverse relationship between presence of various cancers and dietary carotenoids or blood carotenoid levels. However, three out of four intervention trials using high dose beta-carotene supplements did not show protective effects against cancer or cardiovascular disease. Rather, the high risk population (smokers and asbestos workers) in these intervention trials showed an increase in cancer and angina cases. It appears that carotenoids (including beta-carotene) can promote health when taken at dietary levels, but may have adverse effects when taken in high dose by subjects who smoke or who have been exposed to asbestos. It will be the task of ongoing and future studies to define the populations that can benefit from carotenoids and to define the proper doses, lengths of treatment, and whether mixtures, rather than single carotenoids (e.g. beta-carotene) are more advantageous.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Nutritional biomarkers in Alzheimer's disease: the association between carotenoids, n-3 fatty acids, and dementia severity. Abstract of the paper: Carotenoids are fat-soluble antioxidants that may protect polyunsaturated fatty acids, such as n-3 fatty acids from oxidation, and are potentially important for Alzheimer's disease (AD) prevention and treatment. Fasting plasma carotenoids were measured in 36 AD subjects and 10 control subjects by HPLC. Correlations between plasma carotenoid levels, red blood cell (RBC) n-3 fatty acids, and dementia severity were examined in AD patients. Moderately severe AD patients (MMSE=16-19) had much lower plasma levels of two major carotenoids: lutein and beta-carotene, compared to mild AD patients (MMSE=24-27) or controls. Among AD patients, variables (lutein, beta-carotene, RBC docosahexaenoic acid (DHA) and LDL-cholesterol) were significantly correlated with MMSE. A lower MMSE score was associated with lower lutein, beta-carotene and RBC DHA levels, and a higher LDL-cholesterol level. These variables explained the majority of variation in dementia severity (55% of variance in MMSE). Lutein, beta-carotene and beta-cryptoxanthin were positively correlated with RBC DHA in AD patients. The association between higher carotenoids levels and DHA and higher MMSE scores, supports a protective role of both types of nutrients in AD. These findings suggest targeting multiple specific nutrients, lutein, beta-carotene, and DHA in strategies to slow the rate of cognitive decline.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Carotenoid, tocopherol, and retinol concentrations in elderly human brain. Abstract of the paper: BACKGROUND Antioxidants, such as tocopherols and carotenoids, have been implicated in the prevention of degenerative diseases. Although correlations have been made between diseases and tissue levels of antioxidants, to date there are no reports of individual carotenoid concentrations in human brain. OBJECTIVE To measure the major carotenoids, tocopherols, and retinol in frontal and occipital regions of human brain. DESIGN Ten samples of brain tissue from frontal lobe cortex and occipital cortex of five cadavers were examined. Sections were dissected into gray and white matter, extracted with organic solvents, and analyzed by HPLC. RESULTS At least 16 carotenoids, 3 tocopherols, and retinol were present in human brain. Major carotenoids were identified as lutein, zeaxanthin, anhydrolutein, alpha- cryptoxanthin, beta- cryptoxanthin, alpha-carotene, cis- and trans-betacarotene, and cis- and trans-lycopene. Xanthophylls (oxygenated carotenoids) accounted for 66-77% of total carotenoids in all brain regions examined. Similar to neural retina, the ratio of zeaxanthin to lutein was high and these two xanthophylls were significantly correlated (p <0.0001). The tocopherol isomers occurred in the brain over a wider range of mean concentrations (0.11-17.9 nmol/g) than either retinol (87.8 - 163.3 pmol/g) or the identified carotenoids (1.8-23.0 pmol/g). CONCLUSIONS The frontal cortex, generally vulnerable in Alzheimer's disease, had higher concentrations of all analytes than the occipital cortex which is generally unaffected. Moreover, frontal lobes, but not occipital lobes, exhibited an age-related decline in retinol, total tocopherols, total xanthophylls and total carotenoids. The importance of these differences and the role(s) of these antioxidants in the brain remain to be determined.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Dietary carotenoids and cognitive function among US adults, NHANES 2011-2014. Abstract of the paper: Objectives: Dietary carotenoids may limit neuronal damage from free radicals, potentially serving as a modifiable risk factor for cognitive decline. We examined intake of lutein and zeaxanthin (L and Z) in relation to cognitive performance among 2011-2014 National Health and Nutrition Examination Survey participants aged ≥60 years. Methods: L and Z intake from foods and supplements was estimated from two non-consecutive 24-hour diet recalls. Outcomes included the CERAD Word Learning sub-test score, Animal Fluency test score, and Digit Symbol Substitution test score. Regression models were adjusted for survey design variables, year, sex, age, race/ethnicity, body mass index, family income, education, alcohol, and smoking. Results: Among the 2796 participants, higher dietary intake of L and Z was associated with higher score on each test. For example, the highest quartile of L and Z intake was associated with a 2.52 point increase (SE=0.86 points, P=0.01) on the digit symbol score test, compared with the lowest quartile. There were differences by race/ethnicity, with positive associations generally stronger for Black compared to white participants. Discussion: Further research from longitudinal studies is needed, but increasing L and Z intake may help to prevent or slow cognitive decline.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Dietary Carotenoid Roles in Redox Homeostasis and Human Health. Abstract of the paper: Classic nutrition believed that healthy diets should simply provide sufficient antioxidant loads to organisms, to hamper free radical processes and avoid oxidative stress. Current redox biology was proven much more intricate. Carotenoids are bioactive compounds in the human diet with a multifaceted role in redox metabolism. This perspective discusses the participation of α/β-carotene, lutein, zeaxanthin, lycopene, β-cryptoxanthin, astaxanthin, and derivatives in redox homeostasis focusing on (i) their antioxidant/pro-oxidant activities, (ii) control of gene expression via Nrf2-Keap1 and NF-κB pathways, and (iii) their link with (sub)cellular redox circuits, as part of the "redox code" that orchestrates physiological processes and health in humans.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: A possible role for lutein and zeaxanthin in cognitive function in the elderly. Abstract of the paper: Epidemiologic studies suggest that dietary lutein and zeaxanthin may be of benefit in maintaining cognitive health. Among the carotenoids, lutein and zeaxanthin are the only two that cross the blood-retina barrier to form macular pigment (MP) in the eye. They also preferentially accumulate in the human brain. Lutein and zeaxanthin in macula from nonhuman primates were found to be significantly correlated with their concentrations in matched brain tissue. Therefore, MP can be used as a biomarker of lutein and zeaxanthin in primate brain tissue. This is of interest given that a significant correlation was found between MP density and global cognitive function in healthy older adults. An examination of a relation between cognition and lutein and zeaxanthin concentrations in the brain tissue of decedents from a population-based study in centenarians found that zeaxanthin concentrations in brain tissue were significantly related to antemortem measures of global cognitive function, memory retention, verbal fluency, and dementia severity after adjustment for age, sex, education, hypertension, and diabetes. In univariate analyses, lutein was related to recall and verbal fluency, but the strength of the associations was attenuated with adjustment for covariates. However, lutein concentrations in the brain were significantly lower in individuals with mild cognitive impairment than in those with normal cognitive function. Last, in a 4-mo, double-blinded, placebo-controlled trial in older women that involved lutein supplementation (12 mg/d), alone or in combination with DHA (800 mg/d), verbal fluency scores improved significantly in the DHA, lutein, and combined-treatment groups. Memory scores and rate of learning improved significantly in the combined-treatment group, who also showed a trend toward more efficient learning. When all of these observations are taken into consideration, the idea that lutein and zeaxanthin can influence cognitive function in older adults warrants further study.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer's disease: a meta-analysis. Abstract of the paper: In view of the vital role of oxidative stress in the pathogenesis of Alzheimer's disease (AD), the potential of antioxidant supplements to prevent AD have gained much interest, while there are conflicting results on this topic in recent years. The purpose of the present study is to comprehensively evaluate the association between dietary intakes, instead of supplements, of the most common three antioxidants (vitamin E, vitamin C, and β-carotene) and the risk of AD on the basis of the meta-analysis studies published up to October 2011 in Medline and Scopus databases. In total, seven articles were included in the meta-analysis. According to the pooled relative risk [(95% CI) 0.76 (0.67-0.84) for vitamin E, 0.83 (0.72-0.94) for vitamin C, and 0.88 (0.73-1.03) for β-carotene], dietary intakes of the three antioxidants can lower the risk of AD, with vitamin E exhibiting the most pronounced protective effects. The findings will be of significance to the prevention and interventional treatment of AD.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease. Abstract of the paper: In order to assess peripheral levels and activities of a broad spectrum of non-enzymatic and enzymatic antioxidants in elderly subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD), plasma levels of water-soluble (Vitamin C and uric acid) and of lipophilic (Vitamin A, Vitamin E and carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as activities of plasma and red blood cell (RBC) superoxide dismutase (SOD) and of plasma glutathione peroxidase (GPx) were measured in 25 patients with MCI, 63 AD patients and 53 controls. Peripheral levels and activities of antioxidants were similarly lower in MCI and AD patients as compared to controls. As MCI may represent a prodromal stage of AD, and oxidative damage appears to occur as one of the earliest pathophysiological events in AD, an increased intake of antioxidants in patients with MCI could be helpful in lowering the risk of conversion to dementia.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: The association of antioxidants and cognition in the Nurses' Health Study. Abstract of the paper: The authors examined long-term antioxidant intake in relation to cognitive decline among older women. Beginning in 1980, Nurses' Health Study (NHS) participants completed dietary assessments every 4 years; in 1995-2001, 16,010 participants aged ≥70 years completed initial cognitive assessments, which were repeated 3 times at 2-year intervals. Long-term antioxidant intake was averaged from 1980 through the time of initial cognitive interviews. Multivariable-adjusted linear regression was used to estimate mean differences in rates of cognitive decline across categories of vitamin E, vitamin C, and carotenoid intake; statistical tests were 2-sided. No associations were evident for vitamin E or total carotenoid intake and cognitive decline (e.g., after multivariable adjustment, P-trend = 0.44 and P-trend = 0.51, respectively, for a global composite score averaging all 6 cognitive tests), although higher lycopene intake and lower vitamin C intake were related to slower cognitive decline. In alternative analyses of overall cognitive status at older ages (averaging all 4 cognitive assessments), results for vitamins E and C were generally null, but higher carotenoid intake was related to better cognition. Overall, long-term vitamin E and C intakes were not consistently related to cognition, although greater consumption of carotenoids may have cognitive benefits in older adults.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: these data do not permit us to assess why these analyte levels are low but the data are consistent with existing lines of evidence Title of the paper: Plasma beta carotene in Alzheimer's disease. Association with cerebrospinal fluid beta-amyloid 1-40, (Abeta40), beta-amyloid 1-42 (Abeta42) and total Tau. Abstract of the paper: We studied the plasma beta carotene concentrations in 40 Alzheimer's disease patients and the association with cerebrospinal fluid beta-amyloid 1-40, (Abeta40), cerebrospinal fluid beta-amyloid 1-42 (Abeta42) and cerebrospinal fluid total Tau. We found that patients with plasma beta carotene levels below the 25th percentile had 55% reduced ratios of Abeta40/Tau and 51% reduced ratios of Abeta 40/Abeta 42 compared with patients in the highest quartile. Mean Tau concentrations in the lowest quartile of plasma beta-carotene levels were 74% higher compared with the highest quartile of plasma beta-carotene levels. Thus, we could demonstrate an statistically significant association between beta carotene levels in plasma and neurochemical markers in the cerebrospinal fluid of Alzheimer's disease patients.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: β-amyloid, microglia, and the inflammasome in Alzheimer's disease. Abstract of the paper: There is extensive evidence that accumulation of mononuclear phagocytes including microglial cells, monocytes, and macrophages at sites of β-amyloid (Aβ) deposition in the brain is an important pathological feature of Alzheimer's disease (AD) and related animal models, and the concentration of these cells clustered around Aβ deposits is several folds higher than in neighboring areas of the brain [1-5]. Microglial cells phagocytose and clear debris, pathogens, and toxins, but they can also be activated to produce inflammatory cytokines, chemokines, and neurotoxins [6]. Over the past decade, the roles of microglial cells in AD have begun to be clarified, and we proposed that these cells play a dichotomous role in the pathogenesis of AD [4, 6-11]. Microglial cells are able to clear soluble and fibrillar Aβ, but continued interactions of these cells with Aβ can lead to an inflammatory response resulting in neurotoxicity. Inflammasomes are inducible high molecular weight protein complexes that are involved in many inflammatory pathological processes. Recently, Aβ was found to activate the NLRP3 inflammasome in microglial cells in vitro and in vivo thereby defining a novel pathway that could lead to progression of AD [12-14]. In this manuscript, we review possible steps leading to Aβ-induced inflammasome activation and discuss how this could contribute to the pathogenesis of AD.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Inflammasome Involvement in Alzheimer's Disease. Abstract of the paper: Inflammasomes are responsible for the maturation of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-18, and IL-33 and activation of inflammatory cell death, pyroptosis. They assemble in response to cellular infection and stress or to tissue damage, promote inflammatory reactions, and are important in regulating innate immunity particularly by acting as platforms for activation of caspase proteases. They appear to be involved in several pathological processes activated by microbes including Alzheimer's disease (AD). Best characterized in microbial pathogenesis is the nucleotide-binding domain and leucine-rich repeat (NLR)-protein 3 (NLRP3) inflammasome. AD is a neurodegenerative condition in which the neuropathological hallmarks are the deposition of amyloid-β (Aβ) and hyperphosphorylated tau protein coated neurofibrillary tangles. For decades, the role of the innate immune system in the etiology of AD was considered less important, but the recently discovered inflammatory genes by genome-wide association studies driving inflammation in this disease has changed this view. Innate immune inflammatory activity in the AD brain can result from the pathological hallmark protein Aβ as well as from specific bacterial infections that tend to possess weak immunostimulatory responses for peripheral blood myeloid cell recruitment to the brain. The weak immunostimulatory activity is a consequence of their immune evasion strategies and survival. In this review we discuss the possibility that inflammasomes, particularly via the NLR family of proteins NLRP3 are involved in the pathogenesis of AD. In addition, we discuss the plausible contribution of specific bacteria playing a role in influencing the activity of the NLRP3 inflammasome to AD progression.

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CitationGPTRetr342

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Inflammasome-mediated innate immunity in Alzheimer's disease. Abstract of the paper: Historically neurodegenerative diseases, Alzheimer's disease (AD) in particular, have been viewed to be primarily caused and driven by neuronal mechanisms. Very recently, due to experimental, genetic, and epidemiologic evidence, immune mechanisms have entered the central stage and are now believed to contribute significantly to risk, onset, and disease progression of this class of disorders. Although immune activation of microglial cells may over time engage various signal transduction pathways, inflammasome activation, which represents a canonical and initiating pathway, seems to be one of the first responses to extracellular β-amyloid (Aβ) accumulation. Here we review the current understanding of inflammasome activation in AD.-Venegas, C., Heneka, M. T. Inflammasome-mediated innate immunity in Alzheimer's disease.

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CitationGPTRetr343

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: The pathogenic role of the inflammasome in neurodegenerative diseases. Abstract of the paper: The inflammasome is a large macromolecular complex that contains multiple copies of a receptor or sensor of pathogen-derived or damage-derived molecular patterns, pro-caspase-1, and an adaptor called ASC (apoptotic speck containing protein with a CARD), which results in caspase-1 maturation. Caspase-1 then mediates the release of pro-inflammatory cytokines such as IL-1β and IL-18. These cytokines play critical roles in mediating immune responses during inflammation and innate immunity. Broader studies of the inflammasome over the years have implicated their roles in the pathogenesis of a variety of inflammatory diseases. Recently, studies have shown that the inflammasome modulates neuroinflammatory cells and the initial stages of neuroinflammation. A secondary cascade of events associated with neuroinflammation (such as oxidative stress) has been shown to activate the inflammasome, making the inflammasome a promising therapeutic target in the modulation of neurodegenerative diseases. This review will focus on the pathogenic role that inflammasomes play in neurologic diseases such as Alzheimer's disease, traumatic brain injury, and multiple sclerosis. We here review the role of the inflammasome in the pathogenesis of traumatic brain injury (TBI). TBI is initiated by physical force exerted to head, resulting in neuronal injury and death. Primary insult is followed by a secondary cascade of events following neuroinflammation such as mitochondrial dysfunction, production of reactive oxygen species, potassium effluxes, and release of circulating DNA. These events can potentially trigger the activation of NLRP3, NLRP1, and AIM2 during TBI but have yet to be confirmed (dashed lines). NLRP3, NLRP1, and AIM2 associate with the adaptor protein ASC, which initiates the cleavage of pro-caspase-1 to the mature form of caspase-1 which cleaves pro-IL-1β and pro-IL-18 into their mature forms of IL-1β and IL-18.

False

CitationGPTRetr344

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Microglial Inflammasome Activation in Penetrating Ballistic-Like Brain Injury. Abstract of the paper: Penetrating traumatic brain injury (PTBI) is a significant cause of death and disability in the United States. Inflammasomes are one of the key regulators of the interleukin (IL)-1β mediated inflammatory responses after traumatic brain injury. However, the contribution of inflammasome signaling after PTBI has not been determined. In this study, adult male Sprague-Dawley rats were subjected to sham procedures or penetrating ballistic-like brain injury (PBBI) and sacrificed at various time-points. Tissues were assessed by immunoblot analysis for expression of IL-1β, IL-18, and components of the inflammasome: apoptosis-associated speck-like protein containing a caspase-activation and recruitment domain (ASC), caspase-1, X-linked inhibitor of apoptosis protein (XIAP), nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3), and gasdermin-D (GSDMD). Specific cell types expressing inflammasome proteins also were evaluated immunohistochemically and assessed quantitatively. After PBBI, expression of IL-1β, IL-18, caspase-1, ASC, XIAP, and NLRP3 peaked around 48 h. Brain protein lysates from PTBI animals showed pyroptosome formation evidenced by ASC laddering, and also contained increased expression of GSDMD at 48 h after injury. ASC-positive immunoreactive neurons within the perilesional cortex were observed at 24 h. At 48 h, ASC expression was concentrated in morphologically activated cortical microglia. This expression of ASC in activated microglia persisted until 12 weeks following PBBI. This is the first report of inflammasome activation after PBBI. Our results demonstrate cell-specific patterns of inflammasome activation and pyroptosis predominantly in microglia, suggesting a sustained pro-inflammatory state following PBBI, thus offering a therapeutic target for this type of brain injury.

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CitationGPTRetr345

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: The role of inflammasome in Alzheimer's disease. Abstract of the paper: Alzheimer's disease (AD) is a chronic, progressive and irreversible neurodegenerative disease with clinical characteristics of memory loss, dementia and cognitive impairment. Although the pathophysiologic mechanism is not fully understood, inflammation has been shown to play a critical role in the pathogenesis of AD. Inflammation in the central nervous system (CNS) is characterized by the activation of glial cells and release of proinflammatory cytokines and chemokines. Accumulating evidence demonstrates that inflammasomes, which cleave precursors of interleukin-1β (IL-1β) and IL-18 to generate their active forms, play an important role in the inflammatory response in the CNS and in AD pathogenesis. Therefore, modulating inflammasome complex assembly and activation could be a potential strategy for suppressing inflammation in the CNS. This review aims to provide insight into the role of inflammasomes in the CNS, with respect to the pathogenesis of AD, and may provide possible clues for devising novel therapeutic strategies.

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CitationGPTRetr346

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: NLRP3 inflammasome activation drives tau pathology. Abstract of the paper: Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline1. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release2. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.

True

CitationGPTRetr347

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Inflammasomes as therapeutic targets for Alzheimer's disease. Abstract of the paper: Alzheimer's disease is the most common form of progressive dementia, typified initially by short term memory deficits which develop into a dramatic global cognitive decline. The classical hall marks of Alzheimer's disease include the accumulation of amyloid oligomers and fibrils, and the intracellular formation of neurofibrillary tangles of hyperphosphorylated tau. It is now clear that inflammation also plays a central role in the pathogenesis of the disease through a number of neurotoxic mechanisms. Microglia are the key immune regulators of the CNS which detect amyloidopathy through cell surface and cytosolic pattern recognition receptors (PRRs) and respond by initiating inflammation through the secretion of cytokines such as interleukin-1β (IL-1β). Inflammasomes, which regulate IL-1β release, are formed following activation of cytosolic PRRs, and using genetic and pharmacological approaches, NLRP3 and NLRP1 inflammasomes have been found to be integral in pathogenic neuroinflammation in animal models of Alzheimer's disease. Therefore, the inflammasomes are very promising novel pharmacological targets which merit further research in the continued endeavor for efficacious therapeutics for Alzheimer's disease.

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CitationGPTRetr348

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: The NLRP3 inflammasome in Alzheimer's disease. Abstract of the paper: Innate immunity and inflammatory response plays an important role in the pathogenesis of Alzheimer's disease (AD). As the major resident immune cells in the brain, microglial cells constantly survey the microenvironment and are activated by and recruited to senile plaques. Subsequently, they can phagocytose amyloid-β (Aβ) and secrete pro-inflammatory cytokines that influence the surrounding brain tissue. Recently, a wealth of information linking the microglia-specific activation of NLRP3 inflammasome to AD pathogenesis has emerged. We review here the activation mechanisms of NLRP3 inflammasome in microglia and several downstream effects in the brain, demonstrating that toxic Aβ peptide can light a fire in NLRP3 inflammasome and eventually induce AD pathology and tissue damage. More importantly, it has been demonstrated that inhibition of NLRP3 could largely protect from memory loss and decrease Aβ deposition in AD transgenic mouse model. So, we further discuss the recent advances and challenges in targeting NLRP3 inflammasome for AD therapy.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: The Role of Neuronal NLRP1 Inflammasome in Alzheimer's Disease: Bringing Neurons into the Neuroinflammation Game. Abstract of the paper: The innate immune system and inflammatory response in the brain have critical impacts on the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). In the central nervous system (CNS), the innate immune response is primarily mediated by microglia. However, non-glial cells such as neurons could also partake in inflammatory response independently through inflammasome signalling. The NLR family pyrin domain-containing 1 (NLRP1) inflammasome in the CNS is primarily expressed by pyramidal neurons and oligodendrocytes. NLRP1 is activated in response to amyloid-β (Aβ) aggregates, and its activation subsequently cleaves caspase-1 into its active subunits. The activated caspase-1 proteolytically processes interleukin-1β (IL-1β) and interleukin-18 (IL-18) into maturation whilst co-ordinately triggers caspase-6 which is responsible for apoptosis and axonal degeneration. In addition, caspase-1 activation induces pyroptosis, an inflammatory form of programmed cell death. Studies in murine AD models indicate that the Nlrp1 inflammasome is indeed upregulated in AD and neuronal death is observed leading to cognitive decline. However, the mechanism of NLRP1 inflammasome activation in AD is particularly elusive, given its structural and functional complexities. In this review, we examine the implications of the human NLRP1 inflammasome and its signalling pathways in driving neuroinflammation in AD.

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CitationGPTRetr350

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Inflammasomes in neuroinflammatory and neurodegenerative diseases. Abstract of the paper: Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid-β, α-synuclein, and prions, that can activate inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host-derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin (IL)-1β and IL-18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS-resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome-targeted strategies that may potentially treat these diseases.

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CitationGPTRetr351

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease. Abstract of the paper: Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was used, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice, the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 days post-injury in R1.40 TBI mice, which was not observed in non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared with non-Tg mice, regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae after TBI and also support recent studies implicating beta-amyloid as an immunomodulator.

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CitationGPTRetr352

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Targeting Inflammasomes to Treat Neurological Diseases. Abstract of the paper: Inflammasomes are multimeric protein complexes that can sense a plethora of microbe- and damage-associated molecular signals. They play important roles in innate immunity and are key regulators of inflammation in health and disease. Inflammasome-mediated processing and secretion of proinflammatory cytokines such as interleukin (IL) 1β and IL-18 and induction of pyroptosis, a proinflammatory form of cell death, have been associated with the development and progression of common immune-mediated and degenerative central nervous system (CNS) diseases such as Alzheimer disease, multiple sclerosis, brain injury, stroke, epilepsy, Parkinson disease, and amyotrophic lateral sclerosis. A growing number of pharmacological compounds inhibiting inflammasome activation and signaling show therapeutic efficacy in preclinical models of the aforementioned disease conditions. Here, we illustrate regulatory mechanisms of inflammasome activation during CNS homeostasis and tissue injury. We highlight the evidence for inflammasome activation as a mechanistic underpinning in a wide range of CNS diseases and critically discuss the promise and potential limitations of therapeutic strategies that aim to inhibit the inflammasome components in neurological disorders. ANN NEUROL 2021;90:177-188.

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CitationGPTRetr353

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: The Role of Microglia and the Nlrp3 Inflammasome in Alzheimer's Disease. Abstract of the paper: Alzheimer's disease (AD) is the most prevalent form of late-onset dementia. AD affects the health of millions of people in the United States and worldwide. Currently, there are no approved therapies that can halt or reverse the clinical progression of AD. Traditionally, AD is characterized first by the appearance of amyloid-β (Aβ) plaques followed by the formation of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (p-tau). These lesions are linked to synapse loss and eventual cognitive impairment. Additionally, microgliosis is consistently found in regions of the brain with AD pathology. The role of microglia in AD onset and progression remains unclear. Several recent reports indicate that the assembly of the multi-protein complex known as the NOD, LRR, and pyrin-domain containing 3 (Nlrp3) inflammasome by microglia results in apoptosis spec-like protein containing a CARD (Asc) spec formation, which then nucleates new Aβ plaques, thus amplifying Aβ-associated pathology. NFTs can also activate the Nlrp3 inflammasome leading to enhanced tau-associated pathology. Here, we will review the role of microglia and the activation of the inflammasome in the innate immune response to AD.

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CitationGPTRetr354

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Investigating Markers of the NLRP3 Inflammasome Pathway in Alzheimer's Disease: A Human Post-Mortem Study. Abstract of the paper: Neuroinflammatory mechanisms with glial cell activation have been implicated in the pathogenic process of Alzheimer's disease (AD). Activation of the NLRP3 inflammasome is an essential component of the neuroinflammatory response. A role for NLRP3 activation in AD is supported by both in vitro and in vivo preclinical studies with little direct investigation of AD brain tissue. RNA expression of genes of three glial cell markers, HLA-DRA, AIF-1 and GFAP; the components of the NLRP3 inflammasome NLRP3, ASC, and caspase-1; and downstream pre-inflammatory cytokines IL-1 β and IL-18, were investigated in the temporal cortex of AD patients and age- and sex-matched controls. Protein expression of GFAP was also assessed. Increases in both mRNA and protein expression were observed for GFAP in AD. There were no significant changes in other NLRP3 activation markers between groups. Our results indicate the involvement of astrocyte activation in AD, particularly in more severe patients. We found no evidence for the specific involvement of the NLRP3 inflammasome.

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CitationGPTRetr355

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Inflammasome signaling at the heart of central nervous system pathology. Abstract of the paper: Neuroinflammation is a complex innate response of neural tissue against harmful effects of diverse stimuli viz., pathogens, damaged cells and irritants within the Central Nervous System (CNS). Studies show that multiple inflammatory mediators including cytokines, chemokines and prostaglandins are elevated in the Cerebrospinal Fluid (CSF) and in post-mortem brain tissues of patients with history of neuroinflammatory conditions as well as neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. The innate immunity mediators in the brain, namely microglia and astrocytes, express certain Pattern Recognition Receptors (PRRs), which are always on 'high-alert' for pathogens or other inflammatory triggers and participate in the assembly and activation of the inflammasome. The inflammasome orchestrates the activation of the precursors of proinflammatory caspases, which in turn, cleave the precursor forms of interleukin-1beta, IL-18 and IL-33 into their active forms; the secretion of which leads to a potent inflammatory response, and/or influences the release of toxins from glial and endothelial cells. Altered expression of inflammasome mediators can either promote or inhibit neurodegenerative processes. Therefore, modulating the inflammasome machinery seems a better combat strategy than summarily suppressing all inflammation in most neuroinflammatory conditions. In the current review we have surveyed the identified triggers and pathways of inflammasome activation and the following events which ultimately accomplish the innate inflammatory response in the CNS, with a goal to provide an analytical insight into disease pathogenesis that might provide cues for devising novel therapeutic strategies.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury. Abstract of the paper: The inflammasome is an intracellular multiprotein complex involved in the activation of caspase-1 and the processing of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. The inflammasome in the central nervous system (CNS) is involved in the generation of an innate immune inflammatory response through IL-1 cytokine release and in cell death through the process of pyroptosis. In this review, we consider the different types of inflammasomes (NLRP1, NLRP2, NLRP3, and AIM2) that have been described in CNS cells, namely neurons, astrocytes, and microglia. Importantly, we focus on the role of the inflammasome after brain and spinal cord injury and cover the potential activators of the inflammasome after CNS injury such as adenosine triphosphate and DNA, and the therapeutic potential of targeting the inflammasome to improve outcomes after CNS trauma.

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CitationGPTRetr357

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: Brain injury, neuroinflammation and Alzheimer's disease. Abstract of the paper: With as many as 300,000 United States troops in Iraq and Afghanistan having suffered head injuries (Miller, 2012), traumatic brain injury (TBI) has garnered much recent attention. While the cause and severity of these injuries is variable, severe cases can lead to lifelong disability or even death. While aging is the greatest risk factor for Alzheimer's disease (AD), it is now becoming clear that a history of TBI predisposes the individual to AD later in life (Sivanandam and Thakur, 2012). In this review article, we begin by defining hallmark pathological features of AD and the various forms of TBI. Putative mechanisms underlying the risk relationship between these two neurological disorders are then critically considered. Such mechanisms include precipitation and 'spreading' of cerebral amyloid pathology and the role of neuroinflammation. The combined problems of TBI and AD represent significant burdens to public health. A thorough, mechanistic understanding of the precise relationship between TBI and AD is of utmost importance in order to illuminate new therapeutic targets. Mechanistic investigations and the development of preclinical therapeutics are reliant upon a clearer understanding of these human diseases and accurate modeling of pathological hallmarks in animal systems.

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CitationGPTRetr358

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target. Abstract of the paper: There is a great clinical need to identify the underlying mechanisms, as well as related biomarkers, and treatment targets, for traumatic brain injury (TBI). Neuroinflammation is a central pathophysiological feature of TBI. NLRP3 inflammasome activity is a necessary component of the innate immune response to tissue damage, and dysregulated inflammasome activity has been implicated in a number of neurological conditions. This paper introduces the NLRP3 inflammasome and its implication in the pathogenesis of neuroinflammatory-related conditions, with a particular focus on TBI. Although its role in TBI has only recently been identified, findings suggest that priming and activation of the NLRP3 inflammasome are upregulated following TBI. Moreover, recent studies utilizing specific NLRP3 inhibitors have provided further evidence that this inflammasome is a major driver of neuroinflammation and neurobehavioral disturbances following TBI. In addition, there is emerging evidence that circulating inflammasome-associated proteins may have utility as diagnostic biomarkers of neuroinflammatory conditions, including TBI. Finally, novel and promising areas of research will be highlighted, including the potential involvement of the NLRP3 inflammasome in mild TBI, how factors such as biological sex may affect NLRP3 activity in TBI, and the use of emerging biomarker platforms. Taken together, this review highlights the exciting potential of the NLRP3 inflammasome as a target for treatments and biomarkers that may ultimately be used to improve TBI management.

False

CitationGPTRetr359

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in tbi several recent studies have documented increased inflammasome activity after injury primarily occurring in activated microglia in ad aβ accumulation within the cns activates microglia resulting in the release of il1β furthermore aβ plaques form as a result of aβ monomers binding to inflammasome components recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia these findings collectively suggest that the main pathomechanisms of ad may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate ad pathology Title of the paper: NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer's Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss. Abstract of the paper: Neuroinflammation is one of the core pathological features of Alzheimer's disease (AD) as both amyloid β (Aβ) and tau monomers and oligomers can trigger the long-term pro-inflammatory phenotype of microglial cells with consequent overactivation of the inflammasomes. To investigate the NLRP1 inflammasome activation in AD, we analyzed the expression of NLRP1, ASC, cleaved gasdermin (cGSDMD), and active caspase-6 (CASP-6) proteins in each hippocampal subdivision (hilar part of CA3, CA2/3, CA1, subiculum) of postmortem tissue of 9 cognitively healthy controls (HC) and 11 AD patients whose disease duration varied from 3 to 7 years after the clinical diagnosis. The total number of neurons, along with the total number of neurofibrillary tangles (NFTs), were estimated in Nissl- and adjacent modified Bielschowsky-stained sections, respectively, using the optical disector method. The same 9 HC and 11 AD cases were additionally semiquantitatively analyzed for expression of IBA1, HLA-DR, and CD68 microglial markers. Our results show that the expression of NLRP1, ASC, and CASP-6 is present in a significantly greater number of hippocampal formation neurons in AD brains compared to controls, suggesting that the NLRP1 inflammasome is more active in the AD brain. None of the investigated inflammasome and microglial markers were found to correlate with the age of the subjects or the duration of AD. However, besides positive correlations with microglial IBA1 expression in the subiculum and with microglial CD68 expression in the CA1 field and subiculum in the AD group, the overall NLRP1 expression in the hippocampal formation was positively correlated with the number of NFTs, thus providing a causal link between neuroinflammation and neurofibrillary degeneration. The accumulation of AT8-immunoreactive phosphorylated tau proteins that we observed at nuclear pores of large pyramidal neurons of the Ammon's horn further supports their role in the extent of neuronal dysfunction and degeneration in AD. This is important because unlike fibrillar amyloid-β deposits that are not related to dementia severity, total NFTs and neuron numbers in the hippocampal formation, especially in the CA1 field, are the best correlates of cognitive deterioration in both human brain aging and AD. Our findings also support the notion that the CA2 field vulnerability is strongly linked to specific susceptibilities to different tauopathies, including primary age-related tauopathy. Altogether, these findings contrast with reports of nonsignificant microglial activation in aged nonhuman primates and indicate that susceptibility to inflammasome activation may render the human brain comparatively more vulnerable to neurodegenerative changes and AD. In conclusion, our results confirm a key role of NLRP1 inflammasome in AD pathogenesis and suggest NLRP1 as a potential diagnostic marker and therapeutic target to slow or prevent AD progression.

False

CitationGPTRetr360

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity. Abstract of the paper: In acute ischaemic brain injury and chronic neurodegeneration, the first step leading to excitotoxicity and cell death is the excessive release of Glu and the prolonged activation of Glu receptors, followed by intracellular calcium overload. There is apparent agreement that glutamatergic transmission via synaptic NMDA receptors (composed of GluN2A subunits) is neuroprotective, whereas transmission via non-synaptic NMDA receptors (composed of GluN2B subunits) is excitotoxic. Extrasynaptic NMDARs activate cell death pathways and may play a key role in Glu-induced excitotoxic neurodegeneration and apoptosis. Accordingly, the function of protective pathways may be impaired by the concomitant blockade of GluN2A-containing receptors. In contrast, the selective inhibition of non-synaptic GluN2B-containing NMDARs may be beneficial in neuroprotection because it can prevent neuronal cell death and thus maintain protective pathways.

True

CitationGPTRetr361

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Glutamate receptors, neurotoxicity and neurodegeneration. Abstract of the paper: Glutamate excitotoxicity is a hypothesis that states excessive glutamate causes neuronal dysfunction and degeneration. As glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), the implications of glutamate excitotoxicity are many and far-reaching. Acute CNS insults such as ischaemia and traumatic brain injury have traditionally been the focus of excitotoxicity research. However, glutamate excitotoxicity has also been linked to chronic neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and others. Despite the continued research into the mechanisms of excitotoxicity, there are currently no pharmacological interventions capable of providing significant neuroprotection in the clinical setting of brain ischaemia or injury. This review addresses the current state of excitotoxic research, focusing on the structure and physiology of glutamate receptors; molecular mechanisms underlying excitotoxic cell death pathways and their interactions with each other; the evidence for glutamate excitotoxicity in acute neurologic diseases; laboratory and clinical attempts at modulating excitotoxicity; and emerging targets for excitotoxicity research.

False

CitationGPTRetr362

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Glutamate and the pathophysiology of hypoxic--ischemic brain damage. Abstract of the paper: Information obtained over the past 25 years indicates that the amino acid glutamate functions as a fast excitatory transmitter in the mammalian brain. Studies completed during the last 15 years have also demonstrated that glutamate is a powerful neurotoxin, capable of killing neurons in the central nervous system when its extracellular concentration is sufficiently high. Recent experiments in a variety of preparations have shown that either blockade of synaptic transmission or the specific antagonism of postsynaptic glutamate receptors greatly diminishes the sensitivity of central neurons to hypoxia and ischemia. These experiments suggest that glutamate plays a key role in ischemic brain damage, and that drugs which decrease the accumulation of glutamate or block its postsynaptic effects may be a rational therapy for stroke.

False

CitationGPTRetr363

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells. Abstract of the paper: A plethora of neurological disorders shares a final common deadly pathway known as excitotoxicity. Among these disorders, ischemic injury is a prominent cause of death and disability worldwide. Brain ischemia stems from cardiac arrest or stroke, both responsible for insufficient blood supply to the brain parenchyma. Glucose and oxygen deficiency disrupts oxidative phosphorylation, which results in energy depletion and ionic imbalance, followed by cell membrane depolarization, calcium (Ca2+) overload, and extracellular accumulation of excitatory amino acid glutamate. If tight physiological regulation fails to clear the surplus of this neurotransmitter, subsequent prolonged activation of glutamate receptors forms a vicious circle between elevated concentrations of intracellular Ca2+ ions and aberrant glutamate release, aggravating the effect of this ischemic pathway. The activation of downstream Ca2+-dependent enzymes has a catastrophic impact on nervous tissue leading to cell death, accompanied by the formation of free radicals, edema, and inflammation. After decades of "neuron-centric" approaches, recent research has also finally shed some light on the role of glial cells in neurological diseases. It is becoming more and more evident that neurons and glia depend on each other. Neuronal cells, astrocytes, microglia, NG2 glia, and oligodendrocytes all have their roles in what is known as glutamate excitotoxicity. However, who is the main contributor to the ischemic pathway, and who is the unsuspecting victim? In this review article, we summarize the so-far-revealed roles of cells in the central nervous system, with particular attention to glial cells in ischemia-induced glutamate excitotoxicity, its origins, and consequences.

False

CitationGPTRetr364

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Role of nonsynaptic GluN2B-containing NMDA receptors in excitotoxicity: evidence that fluoxetine selectively inhibits these receptors and may have neuroprotective effects. Abstract of the paper: In acute ischaemic brain injury and chronic neurodegeneration, the primary step leading to excitotoxicity and cell death is the excessive and/or prolonged activation of glutamate (Glu) receptors, followed by intracellular calcium (Ca(2+)) overload. These steps lead to several effects: a persistent depolarisation of neurons, mitochondrial dysfunction resulting in energy failure, an increased production of reactive oxygen species (ROS), an increase in the concentration of cytosolic Ca(2+) [Ca(2+)]i, increased mitochondrial Ca(2+) uptake, and the activation of self-destructing enzymatic mechanisms. Antagonists for NMDA receptors (NMDARs) are expected to display neuroprotective effects, but no evidence to support this hypothesis has yet been reported. A number of clinical trials using NMDAR antagonists have failed to demonstrate neuroprotective effects, either by reducing brain injury or by preventing neurodegeneration. Recent advances in NMDAR research have provided an explanation for this phenomenon. Synaptic and extrasynaptic NMDARs are composed of different subunits (GluN2A and GluN2B) that demonstrate opposing effects. Synaptic GluN2A-containing and extrasynaptic GluN2B-containing NMDARs have different co-agonists: d-serine for synaptic NMDARs and glycine for extrasynaptic NMDARs. Both co-agonists are of glial origin. The mechanisms of cell destruction or cell survival in response to the activation of NMDAR receptors depend in part on [Ca(2+)]i and the route of entry of this ion and more significantly on the subunit composition and localisation of the NMDARs. While synaptic NMDAR activation is involved in neuroprotection, the stimulation of extrasynaptic NMDARs, which are composed of GluN2B subunits, triggers cell destruction pathways and may play a key role in the neurodegeneration associated with Glu-induced excitotoxicity. In addition, it has been found that synaptic and extrasynaptic NMDA receptors have opposing effects in determining the fate of neurons. This result has led to the targeting of nonsynaptic GluN2B-containing NMDARs as promising candidates for drug research. Under hypoxic conditions, it is likely that the failure of synaptic glutamatergic transmission, the impairment of the GluN2A-activated neuroprotective cascade, and the persistent over-activation of extrasynaptic GluN2B-containing NMDARs lead to excitotoxicity. Fluoxetine, a drug widely used in clinical practice as an antidepressant, has been found to selectively block GluNR2B-containing NMDARs. Therefore, it seems to be a potential candidate for neuroprotection.

True

CitationGPTRetr365

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Abstract of the paper: Excitotoxicity is one of the most extensively studied processes of neuronal cell death, and plays an important role in many central nervous system (CNS) diseases, including CNS ischemia, trauma, and neurodegenerative disorders. First described by Olney, excitotoxicity was later characterized as an excessive synaptic release of glutamate, which in turn activates postsynaptic glutamate receptors. While almost every glutamate receptor subtype has been implicated in mediating excitotoxic cell death, it is generally accepted that the N-methyl-D-aspartate (NMDA) subtypes play a major role, mainly owing to their high calcium (Ca2+) permeability. However, other glutamate receptor subtypes such as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionate (AMPA) or kainate receptors have also been attributed a critical role in mediating excitotoxic neuronal cell death. Although the molecular basis of glutamate toxicity is uncertain, there is general agreement that it is in large part Ca(2+)-dependent. The present review is aimed at summarizing the molecular mechanisms of NMDA receptor and AMPA/kainate receptor-mediated excitotoxic neuronal cell death.

False

CitationGPTRetr366

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. Abstract of the paper: Glutamate neurotransmitter action on postsynaptic receptors is terminated by its clearance from the synaptic cleft by transporter proteins located in neurons and glial cells. Failure of glutamate removal can lead to neuronal death due to its well-known neurotoxic properties. Glutamate transporters are dependent on external Na+, and thus on the activity of Na+/K+ ATPases, which maintain the Na+ concentration gradient. When the energy brain requirements are not fulfilled by the appropriate blood supply of glucose and oxygen, the Na+ gradient collapses leading to impaired glutamate and aspartate removal, or even to the release of these amino acids through the reverse operation of their transporters. Such a scenario would be associated with brain ischemia and hypoglycemia due to the prompt decline in ATP levels. In addition, some evidence suggests that downregulation of glutamate transporters after the ischemic period, or the dysfunction induced by oxidation, contributes to the accumulation of extracellular glutamate and neuronal death. Neuronal damage is associated with excitotoxicity, a type of cell death triggered by the overactivation of glutamate receptors and the loss of calcium homeostasis. Throughout this review we will discuss recent evidence suggesting that failure of glutamate transport during ischemia contributes to the elevation of extracellular glutamate and to the induction of excitotoxicity. We will also discuss the contribution of glial vs. neuronal glutamate transporters in ischemic damage, and the involvement of the different glutamate transporter subtypes. We will focus on experimental data from rodent models, because many of the studies on glutamate transport and ischemic damage have been performed in these animal species.

False

CitationGPTRetr367

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Building a Bridge Between NMDAR-Mediated Excitotoxicity and Mitochondrial Dysfunction in Chronic and Acute Diseases. Abstract of the paper: Glutamate is the major excitatory neurotransmitter in the brain, and it is widely accepted to play a role in synaptic plasticity and excitotoxic cell death. Glutamate binds to several receptors, including ionotropic N-methyl-D-Aspartate receptor (NMDAR), which is essential in synaptic plasticity and excitotoxicity. This receptor is a calcium channel that is located in synaptic and extrasynaptic sites, triggering different signalling cascades in each case. The calcium entry through extrasynaptic NMDARs is linked to calcium overload in the mitochondria in neurons in vitro. The mitochondria, besides their role in ATP production in the cell, participate in calcium homeostasis, acting as a buffering organelle. Disruption of mitochondrial calcium homeostasis has been linked to neuronal death either by triggering apoptosis or driven by the opening of the mitochondrial transition pore. These cell-death mechanisms contribute to the pathophysiology of diverse diseases such as neurodegenerative Alzheimer's disease or Parkinson's disease, and acute neuropathological conditions such as stroke or traumatic brain injury. In this review, we will address the available evidence that positions the mitochondria as an essential organelle in the control of calcium-mediated toxicity, highlighting its role from the perspective of specific NMDAR signalling microdomains at the level of the central synapse.

False

CitationGPTRetr368

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Synaptic NMDA receptors mediate hypoxic excitotoxic death. Abstract of the paper: Excessive NMDA receptor activation and excitotoxicity underlies pathology in many neuropsychiatric and neurological disorders, including hypoxia/ischemia. Thus, the development of effective therapeutics for these disorders demands a complete understanding of NMDA receptor (NMDAR) activation during excitotoxic insults. The extrasynaptic NMDAR hypothesis posits that synaptic NMDARs are neurotrophic/neuroprotective and extrasynaptic NMDARs are neurotoxic. The extrasynaptic hypothesis is built in part on observed selectivity for extrasynaptic receptors of a neuroprotective use-dependent NMDAR channel blocker, memantine. In rat hippocampal neurons, we found that a neuroprotective concentration of memantine shows little selectivity for extrasynaptic NMDARs when all receptors are tonically activated by exogenous glutamate. This led us to test the extrasynaptic NMDAR hypothesis using metabolic challenge, where the source of excitotoxic glutamate buildup may be largely synaptic. Three independent approaches suggest strongly that synaptic receptors participate prominently in hypoxic excitotoxicity. First, block of glutamate transporters with a nonsubstrate antagonist exacerbated rather than prevented damage, consistent with a primarily synaptic source of glutamate. Second, selective, preblock of synaptic NMDARs with a slowly reversible, use-dependent antagonist protected nearly fully against prolonged hypoxic insult. Third, glutamate pyruvate transaminase, which degrades ambient but not synaptic glutamate, did not protect against hypoxia but protected against exogenous glutamate damage. Together, these results suggest that synaptic NMDARs can mediate excitotoxicity, particularly when the glutamate source is synaptic and when synaptic receptor contributions are rigorously defined. Moreover, the results suggest that in some situations therapeutically targeting extrasynaptic receptors may be inappropriate.

False

CitationGPTRetr369

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Molecular mechanisms of calcium-dependent excitotoxicity. Abstract of the paper: Excitotoxicity is thought to be a major mechanism contributing to neurodegeneration during central nervous system ischemia, trauma, and other neurological disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate, the major excitatory neurotransmitter in the mammalian central nervous system. Glutamate activates a number of postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx or efflux. This leads to a disturbance of the intracellular ionic environment, the best characterized feature of which is the influx of sodium, chloride, and Ca2+. An excess of Ca2+ ions then activates intracellular Ca2+-dependent signaling cascades that eventually lead to neuronal cell death. Despite intensive research in the field of Ca2+-dependent neurotoxicity the precise molecular mechanisms leading to cell death remain poorly understood. In particular, the question of the precise relationship between Ca2+ loading and neurotoxicity has been controversial. Many glutamate receptors are clustered and localized at the postsynaptic density. Recently, increasing knowledge of the molecular composition of the postsynaptic density has allowed us to extend our understanding of the molecular mechanisms of Ca2+-dependent excitotoxicity and to propose that distinct, membrane receptor-specific, neurotoxic signaling pathways transduce Ca2+-dependent excitotoxicity. These findings may have significant implications in the search for precisely targeted therapeutic drugs for a range of neurological disorders.

False

CitationGPTRetr370

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Oxidative glutamate toxicity can be a component of the excitotoxicity cascade. Abstract of the paper: Along with ionotropic and metabotropic glutamate receptors, the cystine/glutamate antiporter x(c)(-) may play a critical role in CNS pathology. High levels of extracellular glutamate inhibit the import of cystine, resulting in the depletion of glutathione and a form of cell injury called oxidative glutamate toxicity. Here we show that a portion of the cell death associated with NMDA receptor-initiated excitotoxicity can be caused by oxidative glutamate toxicity. In primary mouse cortical neurons the cell death resulting from the short-term application of 10 microm glutamate can be divided into NMDA and NMDA receptor-independent phases. The NMDA receptor-independent component is associated with high extracellular glutamate and is inhibited by a variety of reagents that block oxidative glutamate toxicity. These results suggest that oxidative glutamate toxicity toward neurons lacking functional NMDA receptors can be a component of the excitotoxicity-initiated cell death pathway.

False

CitationGPTRetr371

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Excitotoxic cell death. Abstract of the paper: Excitotoxicity refers to the ability of glutamate or related excitatory amino acids to mediate the death of central neurons under certain conditions, for example, after intense exposure. Such excitotoxic neuronal death may contribute to the pathogenesis of brain or spinal cord injury associated with several human disease states. Excitotoxicity has substantial cellular specificity and, in most cases, is mediated by glutamate receptors. On average, NMDA receptors activation may be able to trigger lethal injury more rapidly than AMPA or kainate receptor activation, perhaps reflecting a greater ability to induce calcium influx and subsequent cellular calcium overload. It is possible that excitotoxic death may share some mechanisms with other forms of neuronal death.

False

CitationGPTRetr372

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Bioenergetics and glutamate excitotoxicity. Abstract of the paper: Bioenergetic defects and abnormalities in glutamate neurotransmission have both been proposed to play important roles in neurological diseases of varying chronology, etiology and pathology. Recent experimental evidence suggests an intimate relationship between these two systems. Metabolic inhibition predisposes neurons to glutamate-mediated "excitotoxic" damage. The exact mechanism of this increased susceptibility is yet to be defined, but may involve, singly or in combination, decreased voltage-dependent Mg2+ blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, abnormalities in cellular Ca2+ homeostasis, or elevated production of reactive oxygen species. It is believed that enhancement of excitotoxicity by impaired metabolism may be a ubiquitous mechanism of neuronal death in neurological disease. Further elucidation of the exact mechanism of this enhancement may lead to the discovery of new targets for therapeutic intervention.

False

CitationGPTRetr373

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Abstract of the paper: The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor appears to play a pivotal role in enabling glutamate to express its neurotoxic potential in a variety of neurological disorders. Our results show that the transition of glutamate from neurotransmitter to neurotoxin is facilitated when cellular energy is limited in cultured cerebellar neurons. Omission of glucose, exclusion of oxygen, or inclusion of inhibitors of oxidative phosphorylation or of the sodium/potassium pump, enables the excitatory amino acids glutamate or NMDA to express their neurotoxic potential. We interpret these results as demonstrating that glucose metabolism, ATP production, and functioning Na+,K+-ATPases are necessary to generate a resting potential sufficient to maintain the voltage-dependent Mg2+ block of the NMDA receptor channel; relief of the Mg2+ block enables the excitatory amino acids to act persistently at the NMDA receptor, resulting in the opening of ion channels and subsequent neuronal damage. These findings are discussed in the context of perturbations or abnormalities which lead to decreased availability or utilization of glucose and oxygen in the brain which may trigger endogenous excitatory amino acids to become neurotoxic by this mechanism.

False

CitationGPTRetr374

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Role of Glutamate and NMDA Receptors in Alzheimer's Disease. Abstract of the paper: Excitatory glutamatergic neurotransmission via N-methyl-d-aspartate receptor (NMDAR) is critical for synaptic plasticity and survival of neurons. However, excessive NMDAR activity causes excitotoxicity and promotes cell death, underlying a potential mechanism of neurodegeneration occurred in Alzheimer's disease (AD). Studies indicate that the distinct outcomes of NMDAR-mediated responses are induced by regionalized receptor activities, followed by different downstream signaling pathways. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival. In contrast, the activation of extrasynaptic NMDARs promotes cell death and thus contributes to the etiology of AD, which can be blocked by an AD drug, memantine, an NMDAR antagonist that selectively blocks the function of extrasynaptic NMDARs.

False

CitationGPTRetr375

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Distinct roles of synaptic and extrasynaptic NMDA receptors in excitotoxicity. Abstract of the paper: Excitatory synaptic activity governs excitotoxicity and modulates the distribution of NMDA receptors (NMDARs) among synaptic and extrasynaptic sites of central neurons. We investigated whether NMDAR localization was functionally linked to excitotoxicity by perturbing F-actin, a cytoskeletal protein that participates in targeting synaptic NMDARs in dendritic spines. Depolymerizing F-actin did not affect NMDA-evoked whole-cell currents. However, the number of dendritic NMDAR clusters and the NMDAR-mediated component of miniature spontaneous EPSCs were reduced, whereas the number of AMPA receptor clusters and AMPA receptor-mediated component of EPSCs was unchanged. This selective perturbation of synaptically activated NMDARs had no effect on neuronal death or the accumulation of (45)Ca(2+) evoked by applying exogenous NMDA or L-glutamate, which reach both synaptic and extrasynaptic receptors. However, it increased survival and decreased (45)Ca(2+) accumulation in neurons exposed to oxygen glucose deprivation, which causes excitotoxicity by glutamate release at synapses. Thus, synaptically and extrasynaptically activated NMDARs are equally capable of excitotoxicity. However, their relative contributions vary with the location of extracellular excitotoxin accumulation, a factor governed by the mechanism of extracellular neurotransmitter accumulation, not the synaptic activation of NMDARs.

False

CitationGPTRetr376

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Neuroprotection Mediated through GluN2C-Containing N-methyl-D-aspartate (NMDA) Receptors Following Ischemia. Abstract of the paper: Post-ischemic activation of NMDA receptors (NMDARs) has been linked to NMDAR subunit-specific signaling that mediates pro-survival or pro-death activity. Although extensive studies have been performed to characterize the role of GluN2A and GluN2B following ischemia, there is less understanding regarding the regulation of GluN2C. Here, we show that GluN2C expression is increased in acute hippocampal slices in response to ischemia. Strikingly, GluN2C knockout mice, following global cerebral ischemia, exhibit greater neuronal death in the CA1 area of the hippocampus and reduced spatial working memory compared to wild-type mice. Moreover, we find that GluN2C-expressing hippocampal neurons show marked resistance to NMDA-induced toxicity and reduced calcium influx. Using both in vivo and in vitro experimental models of ischemia, we demonstrate a neuroprotective role of GluN2C, suggesting a mechanism by which GluN2C is upregulated to promote neuronal survival following ischemia. These results may provide insights into development of NMDAR subunit-specific therapeutic strategies to protect neurons from excitotoxicity.

False

CitationGPTRetr377

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Abstract of the paper: NMDA (N-methyl-D-aspartate) receptors are a subtype of ionotropic glutamate receptor with an important role in the physiology and pathophysiology of central neurons. Inappropriate levels of Ca(2+) influx through the NMDA receptor can contribute to neuronal loss in acute trauma such as ischaemia and traumatic brain injury, as well as certain neurodegenerative diseases such as Huntington's disease. However, normal physiological patterns of NMDA receptor activity can promote neuroprotection against both apoptotic and excitotoxic insults. As a result, NMDA receptor blockade can promote neuronal death outright or render neurons vulnerable to secondary trauma. Thus responses to NMDA receptor activity follow a classical hormetic dose-response curve: both too much and too little can be harmful. There is a growing knowledge of the molecular mechanisms underlying both the neuroprotective and neurodestructive effects of NMDA receptor activity, as well as the factors that determine whether an episode of NMDA receptor activity is harmful or beneficial. It is becoming apparent that oxidative stress plays a role in promoting neuronal death in response to both hyper- and hypo-activity of the NMDA receptor. Increased understanding in this field is leading to the discovery of new therapeutic targets and strategies for excitotoxic disorders, as well as a growing appreciation of the harmful consequences of NMDA receptor blockade.

False

CitationGPTRetr378

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Vesicular glutamate release from central axons contributes to myelin damage. Abstract of the paper: The axon myelin sheath is prone to injury associated with N-methyl-D-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury. The findings potentially support a rational approach toward a low-impact prophylactic therapy to protect patients at risk of stroke and other forms of excitotoxic injury.

False

CitationGPTRetr379

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: glun2bcontaining enmdars were proposed to be responsible for ischemiainduced excitotoxicity 179 180 and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain Title of the paper: Extrasynaptic NMDA receptor involvement in central nervous system disorders. Abstract of the paper: NMDA receptor (NMDAR)-induced excitotoxicity is thought to contribute to the cell death associated with certain neurodegenerative diseases, stroke, epilepsy, and traumatic brain injury. Targeting NMDARs therapeutically is complicated by the fact that cell signaling downstream of their activation can promote cell survival and plasticity as well as excitotoxicity. However, research over the past decade has suggested that overactivation of NMDARs located outside of the synapse plays a major role in NMDAR toxicity, whereas physiological activation of those inside the synapse can contribute to cell survival, raising the possibility of therapeutic intervention based on NMDAR subcellular localization. Here, we review the evidence both supporting and refuting this localization hypothesis of NMDAR function and discuss the role of NMDAR localization in disorders of the nervous system. Preventing excessive extrasynaptic NMDAR activation may provide therapeutic benefit, particularly in Alzheimer disease and Huntington disease.

False

CitationGPTRetr380

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Building a Bridge Between NMDAR-Mediated Excitotoxicity and Mitochondrial Dysfunction in Chronic and Acute Diseases. Abstract of the paper: Glutamate is the major excitatory neurotransmitter in the brain, and it is widely accepted to play a role in synaptic plasticity and excitotoxic cell death. Glutamate binds to several receptors, including ionotropic N-methyl-D-Aspartate receptor (NMDAR), which is essential in synaptic plasticity and excitotoxicity. This receptor is a calcium channel that is located in synaptic and extrasynaptic sites, triggering different signalling cascades in each case. The calcium entry through extrasynaptic NMDARs is linked to calcium overload in the mitochondria in neurons in vitro. The mitochondria, besides their role in ATP production in the cell, participate in calcium homeostasis, acting as a buffering organelle. Disruption of mitochondrial calcium homeostasis has been linked to neuronal death either by triggering apoptosis or driven by the opening of the mitochondrial transition pore. These cell-death mechanisms contribute to the pathophysiology of diverse diseases such as neurodegenerative Alzheimer's disease or Parkinson's disease, and acute neuropathological conditions such as stroke or traumatic brain injury. In this review, we will address the available evidence that positions the mitochondria as an essential organelle in the control of calcium-mediated toxicity, highlighting its role from the perspective of specific NMDAR signalling microdomains at the level of the central synapse.

False

CitationGPTRetr381

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Differential NMDA receptor-dependent calcium loading and mitochondrial dysfunction in CA1 vs. CA3 hippocampal neurons. Abstract of the paper: Hippocampal CA1 pyramidal neurons are selectively vulnerable to ischemia, while adjacent CA3 neurons are relatively resistant. Although glutamate receptor-mediated mitochondrial Ca(2+) overload and dysfunction is a major component of ischemia-induced neuronal death, no direct relationship between selective neuronal vulnerability and mitochondrial dysfunction has been demonstrated in intact brain preparations. Here, we show that in organotypic slice cultures NMDA induces much larger Ca(2+) elevations in vulnerable CA1 neurons than in resistant CA3. Consequently, CA1 mitochondria exhibit stronger calcium accumulation, more extensive swelling and damage, stronger depolarization of their membrane potential, and a significant increase in ROS generation. NMDA-induced Ca(2+) and ROS elevations were abolished in Ca(2+)-free medium or by NMDAR antagonists, but not by zinc chelation. We conclude that Ca(2)(+) overload-dependent mitochondrial dysfunction is a determining factor in the selective vulnerability of CA1 neurons.

False

CitationGPTRetr382

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity. Abstract of the paper: In acute ischaemic brain injury and chronic neurodegeneration, the first step leading to excitotoxicity and cell death is the excessive release of Glu and the prolonged activation of Glu receptors, followed by intracellular calcium overload. There is apparent agreement that glutamatergic transmission via synaptic NMDA receptors (composed of GluN2A subunits) is neuroprotective, whereas transmission via non-synaptic NMDA receptors (composed of GluN2B subunits) is excitotoxic. Extrasynaptic NMDARs activate cell death pathways and may play a key role in Glu-induced excitotoxic neurodegeneration and apoptosis. Accordingly, the function of protective pathways may be impaired by the concomitant blockade of GluN2A-containing receptors. In contrast, the selective inhibition of non-synaptic GluN2B-containing NMDARs may be beneficial in neuroprotection because it can prevent neuronal cell death and thus maintain protective pathways.

False

CitationGPTRetr383

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Abstract of the paper: During ischemic brain injury, glutamate accumulation leads to overstimulation of postsynaptic glutamate receptors with intracellular Ca2+ overload and neuronal cell death. Here we show that glutamate can induce either early necrosis or delayed apoptosis in cultures of cerebellar granule cells. During and shortly after exposure to glutamate, a subpopulation of neurons died by necrosis. In these cells, mitochondrial membrane potential collapsed, nuclei swelled, and intracellular debris were scattered in the incubation medium. Neurons surviving the early necrotic phase recovered mitochondrial potential and energy levels. Later, they underwent apoptosis, as shown by the formation of apoptotic nuclei and by chromatin degradation into high and low molecular weight fragments. These results suggest that mitochondrial function is a critical factor that determines the mode of neuronal death in excitotoxicity.

False

CitationGPTRetr384

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: The quantity of calcium that appears to induce neuronal death. Abstract of the paper: Excessive entry of Ca2+ through the NMDA receptor is thought to be the major cause of glutamate toxicity in brain neurons. However, actual quantitation of the calcium overload has not been achieved. Here we show that the absolute amount of 45Ca2+ taken up via the NMDA receptor correlates quantitatively with the amount of acute cell death in cultured cerebellar granule cells of the rat. Analysis of 9- and 16-day cultures reveals that the NMDA-induced Ca2+ uptake is about the same at these ages, whereas the Ca-dependent lethal process is more developed in the older neurons. The calculated lethal concentration of 45Ca taken up exceeds by approximately 10,000 times the maximal concentration of [Ca2+]i that can be measured by fluorescence imaging. It is suggested that the Ca2+ taken up induces the lethal process in a subcellular structure in which it has been segregated.

False

CitationGPTRetr385

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: The Yin and Yang of NMDA receptor signalling. Abstract of the paper: Ca(2+) entry through the NMDA subtype of glutamate receptors has the power to determine whether neurons survive or die. Too much NMDA receptor activity is harmful to neurons - but so is too little. Is it a case of too much or too little Ca(2+) influx causing cell death or do other factors, such as receptor location or receptor-associated proteins, play a role? Understanding the mechanisms behind this dichotomous signalling is an important area of molecular neuroscience with direct clinical implications.

False

CitationGPTRetr386

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: NMDA receptor-mediated K+ efflux and neuronal apoptosis. Abstract of the paper: Neuronal death induced by activating N-methyl-D-aspartate (NMDA) receptors has been linked to Ca2+ and Na+ influx through associated channels. Whole-cell recording from cultured mouse cortical neurons revealed a NMDA-evoked outward current, INMDA-K, carried by K+ efflux at membrane potentials positive to -86 millivolts. Cortical neurons exposed to NMDA in medium containing reduced Na+ and Ca2+ (as found in ischemic brain tissue) lost substantial intracellular K+ and underwent apoptosis. Both K+ loss and apoptosis were attenuated by increasing extracellular K+, even when voltage-gated Ca2+ channels were blocked. Thus NMDA receptor-mediated K+ efflux may contribute to neuronal apoptosis after brain ischemia.

False

CitationGPTRetr387

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Abstract of the paper: Excitotoxicity is one of the most extensively studied processes of neuronal cell death, and plays an important role in many central nervous system (CNS) diseases, including CNS ischemia, trauma, and neurodegenerative disorders. First described by Olney, excitotoxicity was later characterized as an excessive synaptic release of glutamate, which in turn activates postsynaptic glutamate receptors. While almost every glutamate receptor subtype has been implicated in mediating excitotoxic cell death, it is generally accepted that the N-methyl-D-aspartate (NMDA) subtypes play a major role, mainly owing to their high calcium (Ca2+) permeability. However, other glutamate receptor subtypes such as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionate (AMPA) or kainate receptors have also been attributed a critical role in mediating excitotoxic neuronal cell death. Although the molecular basis of glutamate toxicity is uncertain, there is general agreement that it is in large part Ca(2+)-dependent. The present review is aimed at summarizing the molecular mechanisms of NMDA receptor and AMPA/kainate receptor-mediated excitotoxic neuronal cell death.

False

CitationGPTRetr388

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Abstract of the paper: NMDA (N-methyl-D-aspartate) receptors are a subtype of ionotropic glutamate receptor with an important role in the physiology and pathophysiology of central neurons. Inappropriate levels of Ca(2+) influx through the NMDA receptor can contribute to neuronal loss in acute trauma such as ischaemia and traumatic brain injury, as well as certain neurodegenerative diseases such as Huntington's disease. However, normal physiological patterns of NMDA receptor activity can promote neuroprotection against both apoptotic and excitotoxic insults. As a result, NMDA receptor blockade can promote neuronal death outright or render neurons vulnerable to secondary trauma. Thus responses to NMDA receptor activity follow a classical hormetic dose-response curve: both too much and too little can be harmful. There is a growing knowledge of the molecular mechanisms underlying both the neuroprotective and neurodestructive effects of NMDA receptor activity, as well as the factors that determine whether an episode of NMDA receptor activity is harmful or beneficial. It is becoming apparent that oxidative stress plays a role in promoting neuronal death in response to both hyper- and hypo-activity of the NMDA receptor. Increased understanding in this field is leading to the discovery of new therapeutic targets and strategies for excitotoxic disorders, as well as a growing appreciation of the harmful consequences of NMDA receptor blockade.

False

CitationGPTRetr389

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Excitotoxic cell death. Abstract of the paper: Excitotoxicity refers to the ability of glutamate or related excitatory amino acids to mediate the death of central neurons under certain conditions, for example, after intense exposure. Such excitotoxic neuronal death may contribute to the pathogenesis of brain or spinal cord injury associated with several human disease states. Excitotoxicity has substantial cellular specificity and, in most cases, is mediated by glutamate receptors. On average, NMDA receptors activation may be able to trigger lethal injury more rapidly than AMPA or kainate receptor activation, perhaps reflecting a greater ability to induce calcium influx and subsequent cellular calcium overload. It is possible that excitotoxic death may share some mechanisms with other forms of neuronal death.

True

CitationGPTRetr390

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Molecular mechanisms of calcium-dependent excitotoxicity. Abstract of the paper: Excitotoxicity is thought to be a major mechanism contributing to neurodegeneration during central nervous system ischemia, trauma, and other neurological disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate, the major excitatory neurotransmitter in the mammalian central nervous system. Glutamate activates a number of postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx or efflux. This leads to a disturbance of the intracellular ionic environment, the best characterized feature of which is the influx of sodium, chloride, and Ca2+. An excess of Ca2+ ions then activates intracellular Ca2+-dependent signaling cascades that eventually lead to neuronal cell death. Despite intensive research in the field of Ca2+-dependent neurotoxicity the precise molecular mechanisms leading to cell death remain poorly understood. In particular, the question of the precise relationship between Ca2+ loading and neurotoxicity has been controversial. Many glutamate receptors are clustered and localized at the postsynaptic density. Recently, increasing knowledge of the molecular composition of the postsynaptic density has allowed us to extend our understanding of the molecular mechanisms of Ca2+-dependent excitotoxicity and to propose that distinct, membrane receptor-specific, neurotoxic signaling pathways transduce Ca2+-dependent excitotoxicity. These findings may have significant implications in the search for precisely targeted therapeutic drugs for a range of neurological disorders.

False

CitationGPTRetr391

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity. Abstract of the paper: Overactivation of NMDA receptors (NMDARs) is a critical early step in glutamate-evoked excitotoxic injury of CNS neurons. Distinct NMDAR-coupled pathways specified by, for example, receptor location or subunit composition seem to govern glutamate-induced excitotoxic death, but there is much uncertainty concerning the underlying mechanisms of pathway selection. Here we ask whether, and if so how, route-specific vulnerability is coupled to Ca(2+) overload and mitochondrial dysfunction, which is also a known, central component of exitotoxic injury. In cultured hippocampal neurons, overactivation of only extrasynaptic NMDARs resulted in Ca(2+) entry strong enough to promote Ca(2+) overload, which subsequently leads to mitochondrial dysfunction and cell death. Receptor composition per se appears not to be a primary factor for specifying signal coupling, as NR2B inhibition abolished Ca(2+) loading and was protective only in predominantly NR2B-expressing young neurons. In older neurons expressing comparable levels of NR2A- and NR2B-containing NMDARs, amelioration of Ca(2+) overload required the inhibition of extrasynaptic receptors containing both NR2 subunits. Prosurvival synaptic stimuli also evoked Ca(2+) entry through both N2A- and NR2B-containing NMDARs, but, in contrast to excitotoxic activation of extrasynaptic NMDARs, produced only low-amplitude cytoplasmic Ca(2+) spikes and modest, nondamaging mitochondrial Ca(2+) accumulation. The results--showing that the various routes of excitotoxic Ca(2+) entry converge on a common pathway involving Ca(2+) overload-induced mitochondrial dysfunction--reconcile and unify many aspects of the "route-specific" and "calcium load-dependent" views of exitotoxic injury.

False

CitationGPTRetr392

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Calcium, ischemia and excitotoxicity. Abstract of the paper: The initial reports regarding a cytotoxic role of calcium ions were published over 30 years ago. In neurons, calcium ions can gain entry into the cell through several mechanisms. These include the over-activation of glutamate receptors (NMDA, AMPA, KA) or of a range of channels and transporters (TRPM2, TRPM7, NCX, ASICs, CaV1.2, and hemichannels). Potentially toxic cytoplasmic calcium concentrations can also occur due to release from internal stores, either through physical damage to mitochondria and the endoplasmic reticulum, or a malfunction of receptors and channels present in their membranes. Such increases of cytoplasmic calcium concentrations can trigger a range of downstream neurotoxic cascades, including the uncoupling mitochondrial electron transfer from ATP synthesis, and the activation and overstimulation of enzymes such as calpains and other proteases, protein kinases, nitric oxide synthase (NOS), calcineurin and endonucleases. Despite the toxic role of calcium, drugs designed to block its entry into neurons have all failed to have any beneficial effects in clinical trials. We suggest that blocking certain receptors and ion channels is unlikely to be a useful therapeutic strategy due to potential deleterious side effects. However, identifying those that are most responsible for cell death and their downstream signalling pathways may lead to improved strategies for treating ischemic and excitotoxic disorders.

False

CitationGPTRetr393

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Role of Glutamate and NMDA Receptors in Alzheimer's Disease. Abstract of the paper: Excitatory glutamatergic neurotransmission via N-methyl-d-aspartate receptor (NMDAR) is critical for synaptic plasticity and survival of neurons. However, excessive NMDAR activity causes excitotoxicity and promotes cell death, underlying a potential mechanism of neurodegeneration occurred in Alzheimer's disease (AD). Studies indicate that the distinct outcomes of NMDAR-mediated responses are induced by regionalized receptor activities, followed by different downstream signaling pathways. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival. In contrast, the activation of extrasynaptic NMDARs promotes cell death and thus contributes to the etiology of AD, which can be blocked by an AD drug, memantine, an NMDAR antagonist that selectively blocks the function of extrasynaptic NMDARs.

False

CitationGPTRetr394

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Abstract of the paper: Excitotoxicity contributes to neuronal degeneration in many acute CNS diseases, including ischemia, trauma, and epilepsy, and may also play a role in chronic diseases, such as amyotrophic lateral sclerosis (ALS). Key mediators of excitotoxic damage are Ca ions (Ca(2+)), which under physiological conditions govern a multitude of cellular processes, including cell growth, differentiation, and synaptic activity. Consequently, homeostatic mechanisms exist to maintain a low intracellular Ca(2+) ion concentration so that Ca(2+) signals remain spatially and temporally localized. This permits multiple independent Ca-mediated signaling pathways to occur in the same cell. In excitotoxicity, excessive synaptic release of glutamate can lead to the disregulation of Ca(2+) homeostasis. Glutamate activates postsynaptic receptors, including the ionotropic N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) proprionate (AMPA), and kainate receptors. Upon their activation, these open their associated ion channel to allow the influx of Ca(2+) and Na(+) ions. Although physiological elevations in intracellular Ca(2+) are salient to normal cell functioning, the excessive influx of Ca(2+) together with any Ca(2+) release from intracellular compartments can overwhelm Ca(2+)-regulatory mechanisms and lead to cell death. Although Ca(2+) disregulation is paramount to neurodegeneration, the exact mechanism by which Ca(2+) ions actually mediate excitotoxicity is less clear. One hypothesis outlined in this review suggests that Ca(2+)-dependent neurotoxicity occurs following the activation of distinct signaling cascades downstream from key points of Ca(2+) entry at synapses, and that triggers of these cascades are physically co-localized with specific glutamate receptors. Thus, we summarize the importance of Ca(2+) regulation in mammalian neurons and the excitotoxicity hypothesis, and focus on the molecular determinants of glutamate receptor-mediated excitotoxic mechanisms.

False

CitationGPTRetr395

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases. Abstract of the paper: In stroke and neurodegenerative disease, neuronal excitotoxicity, caused by increased extracellular glutamate levels, is known to result in calcium overload and mitochondrial dysfunction. Mitochondrial deficits may involve a deficiency in energy supply as well as generation of high levels of oxidants which are key contributors to neuronal cell death through necrotic and apoptotic mechanisms. Excessive glutamate receptor stimulation also results in increased nitric oxide generation which can be detrimental to cells as nitric oxide interacts with superoxide to form the toxic molecule peroxynitrite. High level oxidant production elicits neuronal apoptosis through the actions of proapoptotic Bcl-2 family members resulting in mitochondrial permeability transition pore opening. In addition to apoptotic responses to severe stress, accumulation of misfolded proteins and high levels of oxidants can elicit endoplasmic reticulum (ER) stress pathways which may also contribute to induction of apoptosis. Two categories of therapeutics are discussed that impact major pro-death events that include induction of oxidants, calcium overload, and ER stress. The first category of therapeutic agent includes the amino acid taurine which prevents calcium overload and is also capable of preventing ER stress by inhibiting specific ER stress pathways. The second category involves N-methyl-D-aspartate receptor (NMDA receptor) partial antagonists illustrated by S-Methyl-N, N-diethyldithiocarbamate sulfoxide (DETC-MeSO), and memantine. DETC-MeSO is protective through preventing excitotoxicity and calcium overload and by blocking specific ER stress pathways. Another NMDA receptor partial antagonist is memantine which prevents excessive glutamate excitation but also remarkably allows maintenance of physiological neurotransmission. Targeting of these major sites of neuronal damage using pharmacological agents is discussed in terms of potential therapeutic approaches for neurological disorders.

False

CitationGPTRetr396

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Calcium-dependent mitochondrial function and dysfunction in neurons. Abstract of the paper: Calcium is an extraordinarily versatile signaling ion, encoding cellular responses to a wide variety of external stimuli. In neurons, mitochondria can accumulate enormous amounts of calcium, with the consequence that mitochondrial calcium uptake, sequestration and release play pivotal roles in orchestrating calcium-dependent responses as diverse as gene transcription and cell death. In this review, we consider the basic chemistry of calcium as a 'sticky' cation, which leads to extremely high bound/free ratios, and discuss areas of current interest or controversy. Topics addressed include methodologies for measuring local intracellular calcium, mitochondrial calcium buffering and loading capacity, mitochondrially directed spatial calcium gradients, and the role of calcium overload-dependent mitochondrial dysfunction in glutamate-evoked excitotoxic injury and neurodegeneration. Finally, we consider the relationship between delayed calcium de-regulation, the mitochondrial permeability transition and the generation of reactive oxygen species, and propose a unified view of the 'source specificity' and 'calcium overload' models of N-methyl-d-aspartate (NMDA) receptor-dependent excitotoxicity. Non-NMDA receptor mechanisms of excitotoxicity are discussed briefly.

False

CitationGPTRetr397

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Mitochondrial membrane potential and the permeability transition in excitotoxicity. Abstract of the paper: Acute neuronal injury caused by activation of glutamate receptors in neurons, or excitotoxicity, can be triggered by the activation of N-methyl-D-aspartate receptors and the entry of large amounts of Ca2+. Recent studies have suggested that mitochondria have a critical role in the excitotoxicity injury mechanism. Mitochondria accumulate large amounts of Ca2+ following glutamate stimulation, and also generate reactive oxygen species. Moreover, the prevention of mitochondrial Ca2+ accumulation protects neurons from injury. The target for the actions of Ca2+ in the mitochondrial matrix has not yet been established. The permeability transition pore has the characteristics of a mechanism that is well suited to mediate neuronal injury. However, evidence for activation of the permeability transition pore in intact neurons is rather indirect, and these data suffer from some ambiguities that make it difficult to conclude that permeability transition is a critical contributor to mitochondrially mediated neuronal injury.

False

CitationGPTRetr398

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: Molecular and cellular mechanisms of excitotoxic neuronal death. Abstract of the paper: Glutamate receptor-mediated excitatory neurotransmission plays a key role in neural development, differentiation and synaptic plasticity. However, excessive stimulation of glutamate receptors induces neurotoxicity, a process that has been defined as excitotoxicity. Excitotoxicity is considered to be a major mechanism of cell death in a number of central nervous system diseases including stroke, brain trauma, epilepsy and chronic neurodegenerative disorders. Unfortunately clinical trials with glutamate receptor antagonists, that would logically prevent the effects of excessive receptor activation, have been associated with untoward side effects or little clinical benefit. Therefore, uncovering molecular pathways involved in excitotoxic neuronal death is of critical importance to future development of clinical treatment of many neurodegenerative disorders where excitotoxicity has been implicated. This review discusses the current understanding of the molecular and cellular mechanisms of excitotoxicity and their roles in the pathogenesis of diseases of the central nervous system.

False

CitationGPTRetr399

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the overstimulation of nmdars results in massive ca2 influx and ca2i overload 211 212 and acute neuronal injury featured by necrotic cell death fig 3 Title of the paper: The overlooked aspect of excitotoxicity: Glutamate-independent excitotoxicity in traumatic brain injuries. Abstract of the paper: Traumatic brain injury (TBI) is a leading major cause of morbidity and mortality in youth and individuals under 45 year age. A wide variety of cellular and molecular mechanisms have been identified contributing to the pathogenesis of TBI. A better understanding of the pathophysiology behind TBI is essential for providing more effective treatment. Excitotoxicity as one of the secondary molecular events is a major contributing factor in apoptosis and neuronal death following the initial injury in TBI. Excitotoxicity is the rapid overload and influx of calcium into the cell cytoplasm, activating a series of deleterious signaling cascades causing the cell to undergo apoptosis. Conventional understanding is that the rapid influx of calcium is initiated through glutamate release. However, there are overlooked glutamate-independent mechanisms that cause the rapid calcium influx into the neuronal cytoplasm, evoking or contributing to excitotoxicity. Therefore, the focus of this review will be on the role of the glutamate-independent excitotoxic mechanisms of the mechanosensitive response of NMDA receptors, mechanoporation of the cell membrane, ischemia, and the release of calcium from intracellular stores. In conclusion, the shear and stretch forces during a TBI event may result in the mechanosensitive activation of NMDA receptors which contribute to glutamate-independent excitotoxicity.

False