bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial Calcium Uniporter Beta in Alzheimer’s Disease
Authors: Kaye Sarah D , Raghav Darpan , Kadam Ashlesha , Elrod John W , Tomar Dhanendra , Jadiya Pooja 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder marked by progressive memory loss and cognitive decline. The precise molecular mechanisms underlying AD pathogenesis remain uncertain, underscoring the need for further investigation to identify novel therapeutic targets. We recently demonstrated that mitochondrial calcium (mCa2+) overload significantly contributes to the development of AD, capable of independently driving AD‐like pathology. Modulating mCa2+ dynamics, such as blocking mCa2+ uptake, holds promise in reducing neuronal cell death in AD. However, these approaches challenge bioenergetic processes due to the role mCa2+ plays in metabolic regulation. Therefore, it is essential to identify a regulator that can maintain mCa2+ homeostasis while preserving bioenergetic functions.MethodsTo identify a new molecular regulatory mechanism for reducing mCa2+ overload and preserving bioenergetics in AD, we focused on Mitochondrial Calcium Uniporter Beta (MCUB), a negative regulator of mCa2+ uptake. Initially, we examined MCUB expression in AD patient samples, AD model mice, and AD cell lines. Observing reduced MCUB expression in AD, we used 5xFAD mutant mice with neuronal‐specific MCUB overexpression to assess age‐associated changes in cognitive function, neuropathology, and mitochondrial bioenergetics. A neuroblastoma cell line expressing human amyloid precursor protein with the Swedish mutation (N2a/APPswe) and adenovirus encoded MCUB was examined for alterations in mitochondrial Ca2+ dynamics and functions.ResultsOur findings revealed that expression of MCUB is lost in non‐familial AD samples, AD mouse models, and AD cell lines. MCUB overexpression in 5xFAD mice rescued spatial and fear‐associated memory impairments and alleviated amyloid beta pathology at 9 months of age. Furthermore, MCUB overexpression mitigated mCa2+ overload, preserved crucial mitochondrial bioenergetic functions including oxidative phosphorylation (OXPHOS) and ATP production, and prevented neuronal cell loss.ConclusionsThis study demonstrates for the first time that modulating MCUB holds therapeutic promise in preserving bioenergetics and mitigating neuronal damage and AD progression. These findings have the potential to significantly advance our understanding of AD pathogenesis and pave the way for effective treatments for AD.
Circular RNA DENND1B contributes to cognitive impairment in Alzheimer’s disease by enhancing blood‐brain barrier permeability via transcellular regulatory axis
Authors: Cheng Zhi , Zhang Yuling , Wang Feng 
Published: January 2025

AbstractBackgroundCircular RNA represents a distinctive form of noncoding RNA resulting from back‐splicing of exons and introns in mRNA. CircRNA has been shown play important roles in neurological diseases, such as Alzheimer’s disease (AD). Some recent studies also have demonstrated circRNA is enriched in the mammal brain and differentially altered during AD. However, little is known the characteristics and functions of key circRNAs directly linked to cognitive of AD. Herein, we identified circDENND1B as a novel circRNA implicated in AD and elucidated its role in cognitive impairment.MethodsWe generated rRNA and linear RNA depleted, and RNA sequencing data from 12‐month‐old 5 × FAD mice hippocampus. The circDENND1B knockdown nanoparticles were applied in 10‐month‐old 5 × FAD mice. The novel object recognition and Morris water maze tests were used to observe cognitive function in these 12‐month‐old mice, and conducting electrophysiological experiments, Golgi‐Cox staining, and measuring blood‐brain barrier permeability improvement also performed in the 5 × FAD mice after circDENND1B knockdown. The fluorescence staining, RNA in situ hybridization, RNA antisense purification, RNA pull‐down, RT‐qPCR, Western blot were quantify the functions of circDENND1B in mice brain and vitro human BBB model.ResultsCircDENND1B, a circRNA enriched in hippocampal neurons, was significantly up‐regulated in AD mice and patients. Knockdown of circDENND1B markedly improved cognitive dysfunctions associated with AD. Additionally we revealed that miR‐17‐5p served as a crucial downstream mediator of circDENND1B‐regulated Blood‐brain barrier (BBB) permeability. Notably, key targets of miR‐17‐5p included lncKCNQ1OT1/VegfA, which involved in the regulation of BBB as well as learning and memory. Overexpression of miR‐17‐5p altered circDENND1B and lncKCNQ1OT1 transcellular shuttling, thereby regulating VegfA expression in brain microvascular endothelial cells leading to changes in BBB permeability.ConclusionIn conclusion, we demonstrated elevated circDENND1B levels in AD patients and provided evidence that the circDENND1B/lncRNA KCNQ1OT1/miR‐17‐5p/VegfA transcellular regulatory axis plays a role in regulating BBB permeability and neuron inflammatory response in both in vivo and in vitro AD models. This identified that circDENND1B/lncRNA KCNQ1OT1/miR‐17‐5p/VegfA transcellular regulatory axis may serve as a novel biomarker for AD, offering new insights for prediction, prognosis, and treatment of AD patients.
Apolipoprotein ε genotype and sex influences skeletal muscle bioenergetic response to diet
Authors: Johnson Chelsea N , Lysaker Colton R , McCoin Colin S , Kemna Riley E , John Casey S. , Thyfault John P , Wilkins Heather M , Geiger Paige C , Morris Jill K 
Published: January 2025

AbstractBackgroundApolipoprotein ε4 (APOE4) is a major risk factor for Alzheimer’s disease (AD). APOE4 carriers display altered whole‐body metabolism, including increased blood glucose and inuslin. Although conditions affecting whole‐body metabolism like obesity and diabetes are AD risk factors, knowledge regarding the contribution of peripheral tissues to this effect is minimal. Skeletal muscle is an important regulator of whole‐body metabolism as a primary site for nutrient oxidation, yet it is unclear if APOE4 affects muscle metabolism. We sought to determine the impact of APOE4 on muscle bioenergetic function.MethodMale and female APOE3 and APOE4 targeted‐replacement mice on a C57BL/6 background (n = 61) from Taconic were fed a high (HFD, 45% fat) or low‐fat diet (LFD, 10% fat) for 4 months before sacrifice. APOE3 mice served as controls because APOE3 does not modify AD risk. At 8‐9 months old, carbohydrate‐driven oxygen consumption in isolated quadriceps mitochondria was measured at basal, state 3 (ADP), state 3 + glutamate, and state 3S (succinate) on the Oroboros Oxygraph‐2k and the gastrocnemius proteome was analyzed on a timsTOF HT mass spectrometer. Mitochondrial‐related metabolic proteins were identified using MitoCarta3.0. Serum lactate was measured using an Abcam kit.ResultAPOE4 associated with differential expression of 49 proteins compared to APOE3 in LFD females only (q‐value <0.05), including reduced levels of proteins involved in oxidative phosphorylation. APOE4 did not affect mitochondrial respiration. HFD altered the expression of 469 proteins in APOE4 females and between 80‐101 proteins in other groups (q‐value <0.05). HFD upregulated proteins involved in lipid metabolism in all groups. HFD upregulated proteins involved in carbohydrate metabolism and increased mitochondrial respiration (basal, p = 0.062; state 3, p = 0.009; state 3 +glutamate, p = 0.032; state 3S, p = 0.17) in APOE4 females only. HFD reduced serum lactate in APOE3 males (p = 0.041), APOE4 males (p = 0.081) and APOE3 females (p = 0.112).ConclusionHFD‐driven upregulation of proteins involved in carbohydrate metabolism in APOE4 female muscle only likely supports increased carbohydrate oxidative capacity and may explain the lack of reduction in serum lactate in this group. Proteomic analysis of human muscle is ongoing to determine if this is reflected in humans.
C‐reactive protein as an inflammatory biomarker for early Alzheimer’s Disease pathogenesis
Authors: Dey Aditi , Kern Silke , Skoog Ingmar 
Published: January 2025

AbstractBackgroundC‐reactive protein (CRP) is an inflammatory biomarker that has been associated with an increased risk of future cognitive decline, alongside other biomarkers such as β‐amyloid (Aβ). We sought to explore the relationship between CRP levels and the amyloid/tau/neurodegeneration (A/T/N) groups in elderly individuals with and without APOE‐ε4.MethodFrom 1203 participants of the Gothenburg H70 Birth Cohort study, born in 1944, plasma CRP levels were collected among 300 participants (159 men & 141 women) who did not have dementia. Cerebrospinal fluid (CSF) levels were taken to create ATN groups and explore their correlation with plasma CRP levels. A linear model was created to analyze mean CRP levels in comparison to varying ATN groups. Additionally, the relationship between CRP levels and participant MMSE scores was analyzed.ResultA negative linear trend was found (p‐value 0.014) with decreasing CRP (0.52 mg/L) in ATN groups with increasing levels of Aβ and p‐tau, meaning CRP decreased as Aβ and p‐tau crossed their respective concentration thresholds to be considered pathological. The A+T+N+ group had lower mean CRP levels than A‐T‐N‐, while the A‐T‐N+ group had higher CRP levels than A‐T‐N‐. Individuals with low Aβ had low CRP more often than those with normal Aβ. No significant difference was found between the mean CRP levels and participants’ MMSE scores (p‐value 0.4117).ConclusionIn conclusion, the results from this study indicate an association between decreasing CRP levels and the progression of early AD pathogenesis. Though elevations in CRP may be a negative prognostic marker in other diseases, associated with brain aging and inflammation, the immune system might be altered depending on the stage of the disease with CRP levels elevated decades before disease onset, decreased years before and during the early stages of the disease, then finally increased again in more advanced stages of the disease. No relationship was found between CRP level and MMSE score.
Cognitive reserve influences symptom onset and longitudinal decline in Dominantly Inherited Alzheimer's Disease
Authors: Llibre‐Guerra Jorge J. , Lu Ruijin , Renton Alan E. , Gordon Brian A. , Benzinger Tammie L.S. , Aschenbrenner Andrew J. , Hassenstab Jason J. , Xiong Chengjie , Perrin Richard J. , Ibanez Laura , Goate Alison M. , Cruchaga Carlos , Morris John C. , Daniels Alisha , McDade Eric , Bateman Randall J. 
Published: January 2025

AbstractBackgroundCognitive reserve (CR) has emerged as a critical factor in understanding clinical‐cognitive heterogeneity in Alzheimer’s disease (AD). However, there is limited evidence of the effect of CR during asymptomatic phases of the disease, age at symptom onset (AAO) and longitudinal decline. In this study, we elucidate the impact of CR on AAO and decline rate using Dominantly Inherited Alzheimer’s Disease (DIAD) as a disease progression model.MethodsDIAD participants were selected from the Dominantly Inherited Alzheimer Network (DIAN) study1. Using structural equation models, we utilized a residual approach to quantify CR. Variance in DIAN cognitive composite2 was decomposed into three latent components (Figure 1): demographic component (CogD), biomarker component (CogB), and reserve component (CogR). CogD refers to variance in the cognitive composite explained by demographic factors. CogB refers to the variance explained by AD biomarkers and markers of neurodegeneration. CogR represents the residual variance in the cognitive composite not explained by CogD or CogB. We examined the relationship between these components and clinical outcomes, including AAO, Clinical Dementia Rating®‐Sum of Boxes (CDR®‐SB), and transition from asymptomatic (CDR = 0) to symptomatic (CDR>0).Results319 participants (asymptomatic mutation carriers [aMC] n = 204, symptomatic MC [sMC] n = 115) were included in the analysis. Individuals with higher baseline CogR had greater odds ratio (OR) of remaining asymptomatic. For the aMC, after adjusting by mutation mean AAO3, one SD increase in the CogR component would multiply the OR of being CDR‐SB = 0 by 4.06 (95%CI 1.8‐8.9), while one SD increase in CogD and CogB component will multiply the OR by 2.6 (95%CI 1.1‐6.2) and 5.16 (95% CI 2.0‐13.3), respectively. For sMC, only the CogR and the CogB components were significant. One SD increase in CogR and CogB corresponds to 0.81 (95%CI 0.72‐0.92) and 0.60 (95%CI 0.50‐0.71) fold decrease in baseline CDR‐SB, respectively. Longitudinally, higher CogR values significantly predicted protection against conversion to CDR >0 and slower progression on CDR‐SB.ConclusionsCR significantly modifies both AAO and rate of clinical decline in DIAD. These findings highlight CR as a factor in AD progression and suggest potential avenues for intervention by enhancing CR to delay onset.
Evaluation of the effects of a calcineurin inhibitor in experimental models of Alzheimer’s disease
Authors: Santos Sarah Tavares Araújo , Gomes Giovanni Freitas , Rocha Nádia Gomes , Oliveira Antônio Carlos Pinheiro 
Published: January 2025

AbstractBackgroundCalcineurin, a protein involved in functions such as synaptic plasticity and neuronal survival, plays an important role in the pathophysiology of Alzheimer’s disease. This study, randomized, investigated the effects of FK506 (FK), a calcineurin inhibitor, on the behavioral, histological, and biochemical alterations observed in models of neurotoxicity induced by NMDA or Aβ and in a transgenic model for AD, in addition to the organotypic culture model stimulated with NMDA.MethodsThis study involved models for AD to experiment injecting NMDA or Aβ1‐42 into the hippocampus of male C57Bl/6 mice aged 8‐12 weeks to induce a neurotoxicity model, treating double‐transgenic APP/PS1 mice, expressing both mouse/human APP and mutant human PS1, with chronic FK506 for AD, in which, to enable NMDA or Aβ1‐42 microinjections, another experiment including a stereotaxic surgery was performed on the C57Bl/6 mice. FK506 doses and the pre‐treatment time were chosen based on prior related studies and its ability to cross the BBB. To obtain organotypic cultures, animals aged between 1 and 3 days were used. Their hippocampi were dissected in an ice‐cold culture and then stimulated with NMDA, which is neurotoxic, or PBS, having previously been inserted into a medium containing FK506 or a negative control. In addition, the microglia depletor clodronate disodium was added to the hippocampal slices. The exploratory open field task, the elevated plus maze (LCE), the interaction test (IS) and social memory and ORT were used to evaluate behavior. To complement the results, real‐time quantitative PCR and a statistical analysis of the data were carried out.ResultsFK506 played a protective role in cognitive impairment in both in vivo models and reduced FJC labeling and microgliosis in the Aβ model. FK506 also prevented the reduction of NeuN, a mature neuron marker, expression in organotypic cultures stimulated with NMDA. Furthermore, chronic treatment with FK506 protected against the behavioral alterations observed in LCE and IS. In addition, FK506 reduced microgliosis in the hippocampus of APP/PS1 animals.ConclusionTogether, these results demonstrate the protective potential of FK506 against the pathology observed in AD models.
Associations of CSF Angiogenic Factors with Cerebrovascular Lesion in Alzheimer’s Disease
Authors: Lin Jun , Shi Jiong 
Published: January 2025

AbstractBackgroundMounting evidence suggests an increase in angiogenesis in the Alzheimer’s disease (AD) brain, but the role of this process in AD remains uncertain. The present study aims to explore the association between CSF angiogenic factors that promote angiogenesis and cerebrovascular lesions as well as neurodegeneration.MethodThe cross‐sectional study included 104 individuals with a CDR score of ≤ 0.5 and 96 individuals with a CDR score > 0.5. We measured 12 angiogenic factors using immunoassays. Cerebrovascular lesions were assessed through CSF PDGFRβ, Qalb, and WMH volume, while neurodegeneration was evaluated by cortical thickness and serum NFL. Cognitive function was measured using MMSE.ResultHigher tau pathology showed associations with increased levels of CSF sVEGFRII, VEGF‐C, VEGF‐D, PLGF, Angiopoietin2, and Serpin E1. Although both Aβ pathology and tau pathology were associated with elevated levels of CSF sVEGFRI, sTIE2, and bFGF, the effects of Aβ pathology seemed to be influenced by tau pathology. Moreover, higher levels of sVEGFRII, sTIE2, PLGF, Serpin E1, IL8, and lower levels of VEGF‐C and uPA were linked to increased CSF PDGFRβ, Qalb, or WMH volume. Furthermore, higher levels of sVEGFRI, sTIE2, PLGF, Angiopoietin2, IL8, and lower levels of VEGF‐A and uPA were associated with reduced cortical thickness, increased serum NFL, and decreased MMSE scores.ConclusionTau pathology may play a critical role in regulating the elevated CSF angiogenic factors, which could contribute to cerebrovascular lesions and neurodegeneration in AD. These results highlight the therapeutic potential of inhibiting hypervascularization or promoting the maturation of neonatal blood vessels in AD.
Prodromal stage in Lewy body dementia in a population of Argentina
Authors: Fernandez Maria Cecilia , Berrios Waleska , Campora Nuria , Golimstok Angel 
Published: January 2025

AbstractBackgroundProdromal stage of Lewy Body Dementia (LBD) is characterized by a set of symptoms that do not yet meet the criteria for dementia. These symptoms are caused by changes in the brain that have not yet reached the threshold for triggering the disease in its complete form.Identifying the prodromal stage of neurodegenerative diseases is crucial for early treatment and prevention of progression to a clinical stage. This study aimed to determine the clinical profile in the prodromal stage of LBD in a population of Argentina.MethodOver six months, we recruited subjects with dementia and a control group of individuals without neurocognitive disorder (NC). All participants underwent a comprehensive medical history, neuropsychological tests, and neuroimaging.Dementia patients were divided into two groups: Group 1 consisted of patients with probable DLB according to the consensus criteria of McKeith et al. 2017. Group 2 consisted of patients with Major Neurocognitive Disorder due to Alzheimer’s Disease (AD) according to DSM V criteria.To detect the presence of early clinical signs, we interviewed family members of patients based on central and supportive clinical signs according to Consortium‐DLB 2017 that may have been present up to 20 years before the dementia diagnosis.ResultThe study included 212 participants; 56 were classified as NC, 72 in Group 1, and 84 in Group 2. No significant differences were observed in sociodemographic factors. Notably, LBD patients exhibited a higher frequency of REM sleep behavior disorder (12.5%), visual hallucinations (9.7%), and syncope (9.7%) compared to the other groups, with statistical significance (p<0.01). Other variables did not show significant differences.ConclusionIn this population with LBD, visual hallucinations, syncope, and REM sleep behavior disorder may occur more than 20 years before the onset of dementia and constitute signs of the prodromal stage. Encouraging the search for these symptoms is essential since they are not frequently questioned in patients with mild cognitive complaints.
Altered Hepatic and Cerebral Lipid Mediator Pathways in Alzheimer’s Disease
Authors: Zhou Sitong , Borkowski Kamil , Liang Nuanyi , Beach Thomas G. , Serrano Geidy E , Kim Kyoungmi , Hammock Bruce D. , Newman John W. , Jin Lee‐Way , Maezawa Izumi 
Published: January 2025

AbstractBackgroundInflammation is crucial in Alzheimer’s Disease (AD), where oxidized lipid derivatives of polyunsaturated fatty acids (PUFAs), i.e., oxylipins, are potent modulators. Soluble epoxide hydrolase (sEH), known for converting pro‐resolving epoxy‐fatty acids to pro‐inflammatory dihydroxy‐fatty acids (diols), is upregulated in the AD brain. Recent studies identify AD as a systemic disorder, but peripheral organs are understudied. Given the liver’s pivotal role in metabolizing lipids and circulating lipid mediators’ production, we tested the hypothesis that the inflammatory lipid mediator networks altered in the brain are also perturbed in the liver.MethodAD diagnosis was based on the NIA‐AA guidelines. We analyzed lipid mediators in paired postmortem brain and liver tissues from 16 cognitive normal and 63 AD participants with short postmortem intervals (≤3 hours). Both alkali‐releasable and free oxylipins were measured using LC‐MS/MS‐based methods. Aberrant metabolites associated with AD were identified using analysis of covariance, adjusting for sex, age, BMI, and postmortem interval. Sex differences were explored.ResultIn both the brain and liver of AD participants, we found altered levels of alkali‐releasable ethanolamides, recognized for their neuroprotective and anti‐inflammatory properties. The most significant changes were observed in sEH activities within the AD liver, where pro‐inflammatory diols decreased in alkali‐releasable fractions. This reversely confirms the published results of increased free diols in AD plasma, as the esterified oxylipin pool serves as a reservoir for free oxylipins. These findings suggest that circulating metabolites of sEH and ethanolamides may predict AD pathogenesis. We also found that the decreased level of pro‐inflammatory 20‐HETE in the AD liver, which did not align with our expectations. Moreover, observations hinted at male proneness to inflammation.ConclusionOur data show significant alterations in lipid mediators in both the AD brain and liver, with liver exhibiting the most pronounced changes. This supports AD being a systemic disorder with the potential for liver to regulate brain function via lipid mediators and emphasizes the complexity of lipid metabolism in AD. Sex distinctions underscore the importance of considering it as a variable in future research. Additionally, it highlights the need to explore the biological implications of alkali‐releasable mediators.