bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early lysosome defects precede neurodegeneration with Aβ and tau aggregation
Authors: Lee Eugene , Miller Morgan , Fernandez Marty A. , Berg Elizabeth , Prada Adriana , Silverman Jill , Young‐Pearse Tracy , Morrow Eric 
Published: December 2022

AbstractBackgroundLoss‐of‐function mutations in the X‐linked endosomal Na+/H+ Exchanger 6 (NHE6) cause Christianson syndrome (CS) in males. CS involves endosome dysfunction leading to early cerebellar degeneration, as well as later‐onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in postmortem studies. In addition, there is reported evidence of modulation of amyloid beta (Aβ) levels in experimental models wherein NHE6 expression was targeted. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously‐expressed Aβ and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously‐expressed (non‐transgenic) tau or Aβ.MethodWe generated an NHE6‐null rat model of CS using CRISPR‐Cas9 genome‐editing technologies to study neurodegeneration in CS and the possibility of Aβ and tau pathology.ResultUsing this novel rat model, we were able to follow the sequence of pathogenic events in CS. NHE6‐null rats demonstrate an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observe biochemical and in situ evidence of both Aβ and tau aggregation in the aged NHE6‐null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observe tau deposition in both neurons and glia, as has been reported in CS postmortem studies previously.ConclusionThis new model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously‐expressed Aβ and tau. This NHE6‐null rat will serve as a new robust model for CS. Furthermore, these studies provide evidence for linkages between endo‐lysosome dysfunction and neurodegeneration involving protein aggregations, including Aβ and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer’s Disease and related dementias.
A short computerized cognitive training may affect cortical sources of rsEEG rhythms in Alzheimer’s disease patients
Authors: Lizio Roberta , Percio Claudio Del , Noce Giuseppe , Lopez Susanna , Janson Jessica , Barulli Maria Rosaria , Logroscino Giancarlo , Musaro Cinzia , Scianatico Gaetano , Rossini Paolo Maria , Lacidogna Giardano , Gesualdo Loreto , Ferri Raffaele , Soricelli Andrea , Fraioli Lucia , Stocchi Fabrizio , Vacca Laura , De Pandis Maria Francesca , Babiloni Claudio 
Published: December 2022

AbstractBackgroundPrevious evidence showed abnormal posterior sources of resting‐state electroencephalographic (rsEEG) delta (<4 Hz) and alpha (about 8‐12 Hz) rhythms in patients with Alzheimer's disease (AD) as cortical neural synchronization markers in quiet wakefulness. We tested whether daily computerized cognitive training (CCT), for a short period, with an application of serious games, may affect these mechanisms,MethodClinical and rsEEG data were collected in AD and Parkinson's disease (PD) patients with cognitive deficits and normal elderly (Nold) subjects. The rsEEG data in the patients were recorded before and after the two weeks of computerized cognitive training. Cortical rsEEG sources were estimated by exact low‐resolution brain electromagnetic tomography (eLORETA).ResultAD and PD patients were both characterized by increased performance scores in the execution of the neuropsychological tasks after the CCT program. In AD patients, no statistical difference (p >0.05) was observed in the rsEEG markers after the CCT program. In PD patients, the widespread delta source activities significantly decreased after cognitive training.ConclusionThese preliminary results suggest that the CCT program with this application of serious games differently affects the cortical neural synchronization mechanisms of rsEEG of the AD and PD patients. In the AD patients, it may have no effect, possibly because of the severely compromised integrity of the cholinergic system in those patients.
An introduction to therapeutic challenges of vascular cognitive impairment
Authors: Elahi Fanny M 
Published: December 2022

AbstractBackgroundNeurodegenerative disorders (NDD) are classified based on subtypes of aggregated proteins, regional brain degeneration and associated clinical syndromes. The designation of vascular cognitive impairment, or rather vascular neurodegenerative disorders (VNDD) can apply to any degenerative brain disease where vascular pathologies are considered as drivers of the dysfunction and degeneration. While pathologies can be quantified at autopsy, the diagnosis of VNDD can be made pre‐mortem based on existing vascular risk factors, biomarker abnormalities and presence of neuropsychiatric symptoms. The differences in classification and approach to diagnosis of NDD versus VNDD, however, and the perceived prevalence of none vascular NDD over VNDD pose barriers to therapeutic developments for VNDD. Often, based on A/T/N biomarkers, the pre‐mortem diagnosis of an individual with biomarker abnormalities and cognitive impairment would be AD, even in presence of significant vascular risk factors and imaging biomarker abnormalities.The first question we need to ask is how can we make the diagnosis of VNDD more accurately and more often? The second would be what are the therapeutically targetable cellular and molecular pathologies in VNDD and how diverse is the vascular pathology underpinning neurodegeneration in VNDD? Finally, if we posit that the most therapeutically targetable phase of VNDD is preclinical, prior to clear cognitive deficits, how do we gauge therapeutic efficacy of interventions?MethodWe will review various approaches and designs for therapeutic target discovery in VNDD.ResultWe will also discuss the therapeutic advantages of VNDD.ConclusionA paradigm shift on categorization and related perception of NDD etiologies is needed to propel the field into a productive decade of impactful therapeutic discoveries, both for prevention and treatment.
Melatonin Improved Brain Pathologies and Cognitive Dysfunction in Rats with Trastuzumap‐Induced Chemobrain
Authors: Chunchai Titikorn , Ongnok Benjamin , Pantiya Patcharapong , Arinno Apiwan , Khuanjing Thawatchai , Prathumsap Nanthip , Maneechote Chayadom , Pintana Hiranya , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2022

AbstractBackgroundTrastuzumap (Trz) has been shown to significantly increase the survival rate in human epidermal growth factor receptor (HER2)‐positive breast cancer patients, whereas it also causes neuroinflammation, leading to cognitive impairment, as called “chemobrain”. The exact mechanisms of Trz‐induced chemobrain are not fully understood. Melatonin, a hormone derived from the amino acid tryptophan, has been shown to have the neuroprotection in several pathological conditions. However, the effects of melatonin on brain mitochondrial function, microglial morphology, synaptic plasticity, and cognitive function in Trz‐induced chemobrain have never been investigated.MethodEighteen male Wistar rats were randomly divided into two groups including control group (0.9% NSS, intraperitoneal (i.p.) injection, n=8) and Trz‐treated group (4 mg/kg for 7 days, i.p. injection, n=16). All Trz‐treated rats were randomly divided into two subgroups (n=8/ subgroup) to receive either vehicle (0.9% NSS, daily via oral gavage) or melatonin (10 mg/kg/day, via oral gavage). At the end of experiment protocol, cognitive function was measured, and brains were obtained for further molecular investigation.ResultTrz‐treated rats displayed significantly impaired brain mitochondrial function as indicated by increased ROS production, brain mitochondrial membrane potential change, and brain mitochondrial swelling. These parameters were attenuated in melatonin‐treated Trz‐rats (p<0.05, Figure 1). Consistently, Trz administration decreased microglial complexity, as measured by Sholl analysis, which was ameliorated by melatonin treatment (p<0.05, Figure 1). In addition, the results demonstrated that hippocampal plasticity as indicated by dendritic spine density significantly decreased in Trz‐rats, resulting in cognitive dysfunction as indicated by reducing preferent index of novel object location (NOL) and novel object recognition (NOR) test (p<0.05, Figure 1). Melatonin‐treated Trz‐rats improved hippocampal plasticity by increased dendritic spine density, leading to the improvement of cognition by increased preferent index of NOL and NOR (p<0.05, Figure 1).ConclusionThese findings suggest that melatonin effectively ameliorated cognitive dysfunction in rats with Trz‐induced chemobrain. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for better preventing chemobrain in the future.
An integrated systems‐level analysis of the molecular changes resulting from systemic inflammation and amyloid‐beta immunisation in Alzheimer’s disease
Authors: MacBean Lachlan Ford , Smith Adam R. , Smith Rebecca G. , Boche Delphine , Lunnon Katie 
Published: December 2022

AbstractBackgroundPost‐mortem histological examination of active amyloid‐beta immunisation participant brains revealed changes to Alzheimer’s neuropathology, including high levels of plaque removal and increased microglia phagocytic activity. We hypothesise that there are neuroinflammation‐associated changes to DNA methylation in the post‐mortem brain tissue of the study participants. This study was run in parallel with a study investigating the molecular consequences of systemic infections in AD. As systemic infections are linked to the development and onset of AD; we hypothesise that epigenetic and transcriptomic changes arise in microglia because of systemic inflammation and may drive the progression of AD.MethodPFC and cerebellum tissue was acquired from 16 patients who had received varying doses of the AN‐1792 vaccine or a placebo. PFC tissue was also collected from AD patients who were diagnosed with a systemic infection at time of death (n = 65), AD patients not diagnosed with an infection (n = 70), cognitively normal patients diagnosed with an infection (n = 48). Tissue from cognitively normal patients with no systemic infection diagnosis (n = 66) was also collected, from which age‐matched controls were used for the immunisation study. DNA was extracted from all cases and Infinium methylation EPIC array employed for quantitative interrogation of methylation sites across the genome. Using linear regression analysis, regions of significant differential methylation were identified and annotated to disease relevant genes.ResultEpigenomic analyses have documented differential methylation dynamics in genes previously associated with AD both globally and in glial cells. This study also shows differences in DNA methylation in key genes in systemic infection cases, both in AD and cognitively normal patients, and immunised brain tissue.ConclusionDiscovery of disease‐related methylation dynamics in immunised AD brains indicate a specific regulatory response to amyloid‐beta immunisation. Likewise, differential methylation in immunised and systemic infection cases proposes a role for DNA methylation as a key player in regulating microglial phagocytic activity and suggests key biomarkers as potential therapeutic targets.
Development of NLRP3 inhibitors for intervening in Alzheimer’s disease
Authors: Xu Yiming , Biby Savannah , Zhang Shijun 
Published: December 2022

AbstractBackgroundNLRP3 inflammasome is an essential component of innate immunity, and its dysregulation has been linked to neuroinflammation and the development of neurodegenerative disorders including Alzheimer’s disease. Therefore, NLRP3 inflammasome represents a promising target for effective AD treatment development.MethodBased on our newly identified lead NLRP3 inhibitor, a photoaffinity labeling probe was designed and employed to understand the mechanism of action for inhibitors based on this chemical scaffold using biochemical, biophysical, and molecular biology assays.ResultThe chemical probe can specifically recognize the NLRP3 protein from cell lysates. Photo‐affinity labeling studies using recombinant human NLRP3 protein also showed their interactions, and notably, the mode of action is different than other known NLRP3 inhibitors. Further characterization using FRET confirmed its interaction with the NLRP3 protein. Mass spectrometry analyses of the photo‐affinity labeled NLRP3 protein revealed a novel biding site with the NACHT domain of the NLRP3 protein.ConclusionStudies using a rationally designed photo‐affinity probe based on our lead NLRP3 inhibitor demonstrated that our inhibitors directly bind to the NLRP3 protein via a novel mechanism of action, distinct from other known NLRP3 inhibitors.
Mitochondrial Phenotypes in iPSC AD Models
Authors: Flannagan Kaitlin , Stopperan Julia A. , Troutwine Benjamin R , Lysaker Colton R , Strope Taylor A. , Draper Julia , Shaddy‐Gouvion Cynthia , Vivian Jay , Haeri Mohammad , Wilkins Heather M 
Published: December 2022

AbstractBackgroundMitochondrial dysfunction is observed in Alzheimer’s disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells. We examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. Postmortem brain tissue was used as a comparison.MethodiPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer’s Disease Research Center (KU ADRC) cohort or purchased from WiCell. Postmortem brain samples were from the KU ADRC cohort when available. A total of four non‐demented and four sporadic AD iPSC lines were examined. Postmortem brain tissue was derived from 9 ND and 12 AD subjects. iPSCs were differentiated into neurons, astrocytes, or cerebral organoids using StemCell Technologies protocols and reagents. iPSC derived models and postmortem brain tissue were subjected to mitochondrial respiration analysis using Seahorse XF technology and spectrophotometric COX Vmax assays. iPSC derived neurons and astrocytes underwent fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, and mitophagy levels.ResultiPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects. These results were not observed in astrocytes. Postmortem human brain samples showed reduced COX Vmax in AD subjects. iPSC derived neurons had reduced mitochondrial respiration parameters, mitochondrial mass, mitochondrial membrane potential, and mitochondrial superoxide production. iPSC derived astrocytes had reduced mitochondrial respiration parameters but increased mitochondrial membrane potential and no change in mitochondrial superoxide production.ConclusioniPSC derived models from AD subjects show mitochondrial dysfunction phenotypes like what is observed in postmortem brain. As iPSCs do not maintain their epigenetic signatures after reprogramming the observed phenotypes are likely due to other somatic factors.
Peroxiredoxin 6 Regulates Glia Toxicity in Tau Mediated Neurodegeneration
Authors: Pankiewicz Joanna E. , Lizińczyk Anita M , Franco Leor A. , Sadowski Martin J. 
Published: December 2022

AbstractBackgroundIn Alzheimer’s disease (AD) neurons, which accumulate hyperphosphorylated tau (p‐tau) are associated with neurodegenerative phenotype microglia (MGnD) and A1 neurotoxic astrocytes. MGnD display reduced ability to phagocytose p‐tau aggregates and neuronal remnants, while their pro‐inflammatory character furthers p‐tau accumulation and neuronal demise. Likewise, A1 astrocytes lose their neuron‐supporting function and promote neurodegeneration. Importantly, MGnD and A1 astrocytes reciprocally stimulate their pathological phenotypes. Factors protecting astrocytes form A1 phenotype transformation are unknown. In this work we explored the role of peroxiredoxin (PRDX) 6 in tau mediated neurodegeneration. PRDX6 is an enzymatic protein which in the CNS is unique to astrocytes. It possesses independent glutathione peroxidase and phospholipase 2 enzymatic activities, which confer ability to repair oxidatively damaged cell membranes and cell‐to‐cell signaling.Method
MAPT
P301S mutant mice (PS19/Prdx6
+/+) were once crossed to Prdx6
‐/‐ mice and mice homozygous for the knock‐in of the Prdx6
129X1/SvJ allele overexpressing wild‐type PRDX6 to generate novel PS19/Prdx6
+/‐ and PS19/Prdx6
Tg lines, respectively. Eight weeks old PS19/Prdx6
+/‐, PS19/Prdx6
+/+, and PS19/Prdx6
Tg animals show 0.4:1:2 ratio of Prdx6 brain mRNA level, while levels of hTau and Gfap mRNA remain unchanged. Male mice were neuropathologically characterized at the age of 9.5 months.Result
PS19/Prdx6
+/‐ mice feature increased hippocampal atrophy and ventricular enlargement and greater p‐tau accumulation compared to PS19/Prdx6
+/+ mice. Contrariwise, PS19/Prdx6
Tg animals show attenuated brain atrophy and p‐tau accumulation. The GFAP+ load used as a marker of global astrocytic activation and the C3+/GFAP+ ratio, used as a surrogate A1 phenotype marker, vary inversely with the Prdx6 gene dose. Likewise, the load of IBA1+ microglia vary inversely with the Prdx6 gene dose, while the CD68+/IBA1+ index, which determines relative microglia phagocytic activity, directly correlates with the Prdx6 expression.ConclusionExacerbation of the pathological phenotype in PS19/Prdx6
+/‐ mice reveals a neuroprotective effect of PRDX6 in tau mediated neurodegeneration, while attenuation of pathology in PS19/Prdx6
Tg mice suggests a merit of therapeutic PRDX6 upregulation. PRDX6 endows astrocytes with resistance to A1 phenotype transition. Astrocytic PRDX6 also reprograms microglia by downregulating their global activation level and selectively promoting phagocytic properties. Comparative analysis of astrocytic and microglia transcriptomic markers across PS19/Prdx6
+/‐, PS19/Prdx6
+/+, and PS19/Prdx6
Tg genotypes is underway.
The etiology of blood‐based biomarkers for Alzheimer’s Disease in a population‐based sample of mid to late‐age males
Authors: Gillespie Nathan A. , Rissman Robert A. , Elman Jeremy A. , Reynolds Chandra A. , Panizzon Matthew S. , Lyons Michael J. , Neale Michael C. , Franz Carol E , Kremen William S. 
Published: December 2022

AbstractBackgroundThe amyloid‐tau‐neurodegeneration (ATN) framework has led to an increased focus on Alzheimer’s disease (AD) biomarkers. The costs and invasiveness of methods relying on cerebrospinal fluid or positron emission tomography imaging have led to efforts to develop sensitive blood‐based biomarkers. Although AD is highly heritable, the biometric genetic and environmental etiology of blood‐based biomarkers has never been explored.MethodWe therefore analyzed plasma beta amyloid (Ab40, Ab42, Ab42/40), total Tau (t‐tau), and neurofilament light (NFL) biomarkers based on a sample of 1,050 men aged 60 to 73 years (m=67.1, SD=2.57) from the Vietnam Era Twin Study of Aging (VETSA). Unlike AB and tau, NFL does not define AD; however, as a biomarker of neurodegeneration it serves as the N component in the ATN framework.ResultUnivariate analyses revealed that familial aggregation in Ab42, Ab42/40, t‐tau and NFL could be entirely explained by additive genetic influences accounting for 50% to 56% of the total variance. All remaining variances were unshared or unique environmental influences. For Ab40, additive genetic (31%) and shared environmental (44%) influences both contributed to total variance. In multivariate analyses, genetic influences accounted for 73% to 75% of the variance in the Ab biomarkers and 55% to 57% of the variance in t‐tau and NFL. The same analyses also revealed that Ab40 and Ab42 were statistically genetically identical and moderately correlated in terms of their environmental influences. All other bivariate associations ranged from small to moderate.ConclusionOur findings suggest that plasma biomarkers are heritable and that Ab40 and Ab42 share the same genetic influences. In contrast, genetic influences on plasma t‐tau and NFL are mostly unique and uncorrelated with plasma Ab in early old‐age men.
The rationale behind the IWG criteria for Alzheimer's disease
Authors: Dubois Bruno R 
Published: December 2022

AbstractBackgroundThe development of in‐vivo biomarkers has moved the diagnosis of Alzheimer’s disease from the dementia stage towards the prodromal stage, and has introduced the potential for preclinical diagnosis (ie, before symptom onset). These developments are relevant for the testing of potential therapies for secondary prevention of Alzheimer’s disease.MethodReview of the literatureResultIn 2018, the US National Institute on Aging and the Alzheimer’s Association proposed a purely biological definition of Alzheimer’s disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice, at least for the supposely preclinical stage of the disease. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. This was previously underlined by neuropathologists who indicate a consensus to disentangle the clinic‐pathological term ‘Alzheimer’s disease’ from the presence of Alzheimer lesions in the brain in their ‘NIA‐AA guidelines for the neuropathological assessment of Alzheimer’s disease’. Furthermore, a positive Alzheimer’s disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer’s disease pathology is present as a comorbidity.ConclusionIn line with these observations, the International Working Group recommend that Alzheimer’s disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer’s disease phenotypes, whereas biomarker‐positive cognitively unimpaired individuals should be considered only at‐risk for progression to Alzheimer’s disease.