bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau‐induced astrocyte senescence and dysfunction in AD tauopathy
Authors: Makhlouf Haneen 
Published: January 2025

AbstractBackgroundCellular senescence is defined as cell cycle arrest and the acquisition of a proinflammatory ‘senescence‐associated secretory phenotype’ (SASP). In Alzheimer’s disease (AD), tau protein in neurons undergoes hyperphosphorylation and misfolding, resulting in the formation of pathogenic soluble aggregates known as tau oligomers. Tau oligomers are released from neurons during neuronal activation and are transmitted to postsynaptic cells in a prion‐like fashion. In addition to neurons, tau is expressed in various brain cell types, including astrocytes. In the present study, we tested the central hypothesis that soluble pathogenic tau can be transmitted to astrocytes and that tau transmission to astrocytes induces cytoskeleton destabilization and cellular dysfunction, contributing to the progression of AD.Methodsto test the molecular consequences of tau transmission, we exposed primary human astrocytes with purified tau oligomers and we measured markers of senescence (cell and nuclear size, cell cycle arrest, and SASP activation) using advanced biochemical tools, immunocytochemistry, and live‐cell microscopy. We also measured cell cycle arrest and SASP activation in the whole brain and astrocyte fractions isolated from hTau mice, a mouse model of AD tauopathy. In addition, we co‐cultured human astrocytes undergoing tau‐induced senescence with primary mouse or non‐human primate neurons to determine the impact of senescent astrocytes on neurons (using immunocytochemistry and 3D image analyses to measure aspects of dendrite and spine abundance and morphology).ResultsOur findings reveal that pathogenic soluble tau is readily transmitted to primary human astrocytes in vitro and in vivo and that pathogenic tau transmission triggers phosphorylation of endogenous astrocyte tau, leading to the destabilization of the microtubule cytoskeleton. Further, we found that transmission of pathogenic tau to astrocytes potently upregulated multiple markers of cellular senescence, demonstrating for the first time pathogenic tau‐induced astrocyte senescence. Moreover, density of dendritic spines and dendritic area was pronouncedly decreased in neurons exposed to astrocytes undergoing tau‐induced senescence.ConclusionOur study showed that pathogenic tau is transmitted to cultured human astrocytes and that transmission of pathogenic tau to astrocytes triggers astrocyte senescence in a mouse model of AD tauopathy. Our data suggest that senescent astrocytes may be critical mediators of neuronal dysfunction in AD tauopathy.
Molecular environment in Alzheimer’s disease brain revealed by the hybrid imaging analyses
Authors: Ogawa Tadayuki , Homma‐Takeda Shino , Umemura Tomonari , Hirata Takafumi , Saito Yuko 
Published: January 2025

AbstractBackgroundAlthough amyloid deposition in brain is one of the hallmark pathological features of Alzheimer’s disease (AD), the upstream events and its molecular environment in AD brain remain largely unknown. Recent advances in analytical methods such as mass spectrometry can provide the cutting‐edge tools to unveil the AD pathogenesis at molecular and atomic level.MethodIn order to gain the comprehensive information about AD pathology at molecular level, postmortem brain sections of AD patients were analyzed by the hybrid molecular imaging methods composed of the conventional histological analyses, matrix assisted laser desorption ionization mass spectrometry imaging (MALDI‐MSI) for small molecules, laser ablation inductively coupled plasma mass spectrometry (LA‐ICP‐MS) imaging for metals, and particle induced X‐ray emission (PIXE) imaging for elements. Principal components analysis (PCA) was also applied to discover the differences between the spectra datasets of AD and healthy control brains. Specific distribution of molecules and elements were visualized on the brain slice. (Ethics Approval: Dokkyo Medical University No.2021‐004, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology No.R20‐003).ResultMALDI‐MSI showed abnormal distribution of lipids, such as phospholipids, sphingolipids, and their derivatives in AD brain. LA‐ICP‐MS visualized the distribution of elements, including some metals in the wide‐field brain section. PIXE imaging displayed the specific concentration of atoms nearby the pathological tangles detected by anti‐ubiquitin antibody. PCA proposed the effective classification to distinguish AD from control based on mass spectra.ConclusionOur data suggest the molecular and atomic environment in brain that is closely linked to AD pathology. Further analyses should be conducted to elucidate the fundamental mechanism of AD pathogenesis and prevention.
Tackling selective neuronal vulnerability: Subnuclei involvement of amygdala‐predominant Lewy body disease in early‐onset Alzheimer’s disease
Authors: Fischer D. Luke , VandeVrede Lawren , Seeley William W. , Spina Salvatore , Wekselman Fattin , Lago Argentina Lario , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundLewy body disease (LBD) often co‐occurs with Alzheimer’s (AD), resulting in more significant cognitive decline than AD or LBD alone. LBD’s hallmarks, asyn‐positive Lewy bodies and neurites, propagate from the enteric system or olfactory bulb to the amygdala, which acts as a gatekeeper for spread to other structures. Initially, LBD appears in the central or cortical nuclei, reflecting brainstem or olfactory origins. A third pattern of LBD is quite prevalent in sporadic and familial early‐onset AD (EOAD). This amygdala‐predominant LBD (AP‐LBD) type does not conform with the most used staging systems for LBD and has received little attention. We found a link between asyn seeding‐competent fibrils in cerebrospinal fluid (CSF) and LBD’s transition from the amygdala, supporting its gatekeeper role. The factors enabling asyn propagation in the amygdala remain unknown. Our goal is to map asyn and tau markers in EOAD cases with permissive vs. non‐permissive AP‐LBD in amygdala subnuclei, identifying spread pathways and vulnerable cell populations.MethodWe identified all postmortem EOAD cases with AP‐LBD from the UCSF Neurodegenerative Disease Brain Bank (n = 47), 14 of which have banked CSF for asyn seeding amplification testing. We are using multiplex immunofluorescence to label: phosphorylated asyn; phosphorylated, mis‐conformed, or truncated tau; and all neurons. Markers will be quantified from digital pathology scans, and we will analyze the degree of colocalization by region for the central nucleus, basolateral nuclei, and cortical nucleus.ResultPending analysis, we will report the pattern of LBD across subnuclei. Of eight CSF samples, 37.5% were positive for asyn seeding with six samples pending. Asyn and tau markers by subnucleus will be compared between CSF‐positive and ‐negative cases.ConclusionMapping AP‐LBD across amygdala subnuclei may yield insights into selectively vulnerable neurons. This research has the potential to enhance our understanding of AP‐LBD and its underlying mechanisms, ultimately contributing to the development of more targeted diagnostic and therapeutic strategies in the realm of neurodegenerative diseases.
Understanding the blood‐brain barrier breakdown and vascular dysfunctions in new AD mouse models
Authors: Chiu Yuanpu 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD), the leading cause of dementia accounting for 70% of cases, involves complex pathogenesis with amyloid, tau, and cerebrovascular dysfunction contributing significantly. Vascular changes and impairment are strongly associated with AD pathogenesis in new knock‐in models from the MODEL‐AD consortium – early‐onset AD (EOAD) and late‐onset AD (LOAD) mice – which can be influenced by spatial transcriptomic genetic factors.MethodWe will thoroughly characterize vascular dysfunction in these models over time: 3, 6, 9 months for EOAD mice; 4, 8, 12 months for LOAD mice. Age‐matched C57BL/6J mice will serve as controls. Additionally, we will apply cutting‐edge spatial transcriptomics with subcellular resolution (Stereo‐seq) to one EOAD and one LOAD model to uncover molecular changes underlying neurovascular dysfunction. We will integrate the obtained data with existing resources.ResultThe pathological phenotypes of the new AD mouse models are expected to express microglial responses that are positively correlated with amyloid beta aggregation, leading to tau pathology. Vasculature is also expected to be impaired. The distribution of the phenotypes tends to be in cortical and hippocampal regions.ConclusionOur outcomes will provide an enhanced understanding of blood‐brain barrier (BBB) breakdown and vascular contributions in physiological AD models, guiding future mechanistic and therapeutic studies of vascular‐directed strategies to mitigate neurodegeneration.
Vascular pathology: a key neuropathological feature in young and middle age individuals
Authors: Leite Renata Elaine Paraizo , Socher Karen L R , Rodriguez Roberta Diehl , Brucki Sonia , Ferretti‐Rebustini Renata Eloah de Lucena , Ferriolli Eduardo , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Grinberg Lea T. , Suemoto Claudia Kimie , Nitrini Ricardo 
Published: January 2025

AbstractBackgroundClinicopathological studies suggest a role of minor cerebrovascular changes in the cognitive decline of individuals with a low neurodegenerative burden. However, it remains unclear whether small vascular brain lesions can impact cognition in middle aging individuals. Additionally, recent clinicopathological studies have shown that even a low Alzheimer’s disease (AD) neuropathological burden can significantly impact neuropsychiatric function. This study aims to evaluate the presence of AD neuropathological changes and their relationship with cognitive impairment, neuropsychiatric symptoms and risk factors in a multiethnic group under the age of 65.MethodA post‐mortem study evaluating individuals aged 30‐64 years from the Biobank for Aging Studies at the University of Sao Paulo, Brazil. Neuropathological examinations were carried out based on accepted criteria, using immunohistochemistry. The clinical diagnosis was established through a postmortem interview with an informant using the Cognitive Dementia Rating (CDR). We compared the frequency of neurofibrillary tangles, neuritic plaques, lacunar infarct, hyaline arteriolosclerosis, cerebral amyloid angiopathy, synucleinopathy, and siderocalcinosis between groups. We also described the frequency of neuropathological diagnoses and neuropsychiatric symptoms.ResultAmong participants with neuropathological disease (n = 61), vascular dementia (VaD) was the most frequent diagnosis (42,7%), followed by AD (11,5%) (Figure 1). A higher frequency of vascular pathology (p<0.001) was found in individuals with cognitive impairment (Table 2). Some degree of neurofibrillary pathology was found in 54.2% of the individuals, while neuritic plaques were found in 9.7% of the cases, regardless of the presence of cognitive impairment or neuropsychiatric symptoms. AD‐type pathology burden was higher in individuals with cognitive impairment. The frequency of NPS was higher in CI individuals with significant difference in almost all subitems of the NPI, except in appetite changes. High frequency of cerebrovascular risk factors such as hypertension (60.7%) and smoking (61.1%) was also observed in the entire sample (Table 1).ConclusionOur data show that AD neuropathological changes can begin in mid‐age and corroborate findings from other series predominantly involving older Caucasians with high educational attainment, which have demonstrated the role of vascular pathology in cognitive impairment. As vascular risks are preventable, implementing aggressive measures to reduce these factors may impact the prevalence of cognition‐related dysfunction.
Whole genome sequence‐based association of cognitive decline and retinal thickness in the Japanese population
Authors: Taira Makiko , Fuse Nobuo , Saykin Andrew J. , Nagami Fuji , Kinoshita Kengo , Yamamoto Masayuki 
Published: January 2025

AbstractBackgroundDementia is age‐related with a significant genetic contribution, yet genome‐wide association studies have not fully accounted for heritability. This discrepancy may in part be due to reliance on SNPs and small indels. Whole‐genome sequencing (WGS) data in the Japanese population may reveal population‐specific susceptibility loci for dementia. Retinal imaging with optical coherence tomography (OCT) is noninvasive, reproducible, and can detect thinning associated with progressive neurodegeneration. Association of population‐specific genetic susceptibility loci with retinal thinning and cognitive decline may reveal novel aspects of dementia risk and pathophysiology.MethodAmong participants with WGS data from the Tohoku Medical Megabank Organization (ToMMo) Ophthalmology Study (“ToMMo Eye Study”), individuals with adequate quality data on retinal nerve fiber layer and ganglion cell layer thickness from spectral‐domain optical coherence tomography (SD‐OCT) scans were selected. Since retinal thinning also occurs in glaucoma, we performed a GWAS using age, sex, and 10 principal components as covariates using SAGE1.2 to obtain a set of genes responsible for glaucoma and confirm that the genotyping was successful. We then attempted to identify susceptibility loci for cognitive decline by using (1) the Mini‐Mental State Examination, Japanese version (MMSE‐J), (2) the Montreal Cognitive Assessment, Japanese version (MoCA‐J), and (3) the Mini‐COG© (a simple screening for early detection of dementia, Japanese version) scores as associated factors, respectively. Furthermore, these validation results were also compared with those obtained from GWAS using imputation data performed on custom arrays (Japonica ArrayTM, v2 or NEO) for Japanese.Result84 significant (p < 5.0E‐8) genome‐wide susceptibility loci (hg38) of RNFL were detected on 14K WGS‐based study (the top hit locus: Chr14, SIX6 gene, P = 4.50E‐46). There were many genetic loci that have already been reported to be associated with glaucoma susceptibility, including the above locus. Among the results of GWAS for cognitive decline combining the three cognitive scores after normalization to z‐scores, several loci have shown significant susceptibility in both of RNFL and cognitive rating scale. Some loci suggested more than a high or moderate effect of altering protein efficacy.ConclusionWe present an initial WGS‐based genetic study of retinal thickness and cognitive decline in the Japanese population.
Agitation and mortality in dementia: application of the syndromic International Psychogeriatric Association criteria‐based approach to survival analyses
Authors: Ismail Zahinoor , Hosseinpour Zahra , Hao Chenhui , Goodarzi Zahra , Smith Eric E. , Seitz Dallas 
Published: January 2025

AbstractBackgroundAgitation in dementia is associated with poor outcomes, including mortality. However, the lack of a consensus definition of agitation has hampered research, historically driven by variable approaches to symptom identification. Accordingly, prevalence estimates range widely (5%‐88%) and interventions are hard to compare meaningfully. The International Psychogeriatric Association (IPA) consensus definition advanced the field from a symptomatic to a syndromic criteria‐based approach. As per the validated IPA criteria, agitation behaviors can manifest as verbal aggression (VA), physical aggression (PA), and/or excessive motor activity (EMA). We determined the three‐year mortality rate for syndromic agitation and each of the three IPA agitation domains. We hypothesized 1) higher mortality for those with agitation; and 2) PA would have the highest mortality of the three domains.MethodNational Alzheimer’s Coordinating Center (NACC) participants (n = 3226), with baseline dementia diagnosis were included. Neuropsychiatric Inventory Questionnaire (NPI‐Q) items identified IPA domains as follows: VA (irritability); PA (agitation/aggression); and EMA (aberrant motor activity). Agitation+ status was based on item scores ≥1. Kaplan‐Meier survival curves were used to visualize and compare group trajectories. Cox proportional hazards regressions modelled: 1) three‐year mortality for Agitation±; and 2) three‐year mortality for combinations of agitation domains relative to VA alone, adjusted for age, sex, race, education, and MMSE. To address potential confounding, propensity scores were applied using inverse probability treatment weighting. Sex differences in outcomes across exposure groups were assessed.ResultParticipants (age 74.5±9.7 years, 51% female) who were Agitation+ had a 1.37‐fold higher mortality rate (CI:1.12–1.69, p<0.001) relative to Agitation‐ (Figure 1). Higher agitation‐related mortality was seen in males (HR = 1.52, CI:1.18‐1.97, p = 0.001) and females (HR = 1.51, CI:1.1‐2.06), p<0.001); between‐sex HRs did not differ (multiplicative interaction test HR = 0.97, CI:0.8‐1.17, p = 0.96). Domain analyses revealed 1) generally higher hazards when >1 agitation domain was observed; and 2) higher hazard for mortality for EMA than PA in reference to VA (Figure 2).ConclusionThis study provides further validation of the IPA Agitation criteria and the syndromic approach to agitation in dementia. Previously underappreciated relative to PA, and contrary to our hypothesis, EMA emerged as an important IPA agitation domain, having the greatest mortality risk.
Genetic correlation analysis identifies genetic loci shared between Alzheimer’s disease and primary psychiatric disorders
Authors: Kumar Ajneesh , Ray Nicholas R. , Cuccaro Michael L. , Beecham Gary , Huey Edward D. , Reitz Christiane 
Published: January 2025

AbstractBackgroundNeuropsychiatric Symptoms (NPS) (e.g., aggression, psychosis, anxiety, apathy, depression, agitation, sleep disturbances, repetitive behaviors) occur in 85% of AD patients, and are associated with accelerated decline, out‐of‐home placement, increased costs, and greatly increased suffering of patients and families. Our understanding of the etiology of NPS in AD is inadequate, with treatments for NPS often being ineffective and associated with serious adverse effects. Pharmacological treatments have generally been borrowed from their indications for psychiatric illness, despite limited understanding to what extent the molecular and genetic architectures underlying AD‐associated NPS overlap with that of primary psychiatric disorders.MethodTo characterize the genetic overlap between AD and major psychiatric disorders and identify potentially shared biological processes we conducted local genetic correlation analyses between AD and bipolar disorder, depression, and schizophrenia using LAVA (Local Analysis of [co]Variant Association), capitalizing on the largest most recent GWAS summary statistics for these traits (AD: n = 401,577; bipolar disorder: n = 413,466; depression: n = 1,154,267; schizophrenia: n = 130,644).ResultLocal genetic correlation analyses identified fifteen loci shared between Alzheimer’s disease and depression and two loci shared between AD and bipolar disorder after adjusting for multiple testing. Finemapping and functional analyses of the identified loci are in process.ConclusionThese findings support the notion of genetic overlap between AD and bipolar disorder, and AD and depression, respectively. Functional characterization of these loci will be critical to characterize the specific underlying causative genes and biological processes.
Repeated reactivation of HSV‐1 in mouse brain spreads radially from the trigeminal ganglion, altering expression of synaptic and immune genes in patterns similar to early AD
Authors: Funk Cory C , Darvas Martin , Johnston Christine , Robinson Max , Schaffer Caitlyn , Battaglia Christian , Aubert Martine , Wiley Jesse C 
Published: January 2025

AbstractBackgroundThe immerging role of CD8+T cells, interferon and the adaptive immune response in AD is consistent with previous observations of the putative role of neurotrophic herpesvirus family infections contributing to Alzheimer’s Disease pathophysiology. An outstanding question is how chronic viral infections over decades may contribute to AD pathogenesis. Our HSV‐1 reactivation model aims to provide insights to this question.MethodWe infected 2 month old C57B6/J mice containing humanized APP and APOE4 with 106 PFU HSV‐1 strain 17 via corneal scarification. We reactivated the virus with the bromo‐domain compound JQ1 at 4, 7 and 10 months, with 1x, 3x and 6x reactivations respectively and harvested the brainstem, hippocampus, entorhinal cortex and dural sinuses, for RNAseq. To identify common changes in gene expression between our HSV‐1 reactivation model and AD, we compared the gene expression profiles of our mice to both human and mouse model gene profiles using 19 AD‐specific categories (BioDomains).ResultWe found reactivation by JQ1 resulted in increased HSV‐1 detection by qPCR in a progressive manner, emanating outward from the trigeminal ganglion, towards more distal brain regions. We observed changes in RNAseq expression profiles in a time‐dependent manner, with the greatest number of differentially expressed genes at 7 months. We observed changes in synaptic and immune genes in both the entorhinal cortex and hippocampus. We also saw decreases in gene expression in lipid metabolism, myelination, and the endolysosomal pathways.ConclusionOur HSV‐1 reactivation mouse model identifies changes in gene expression that are similar to those observed in humans and mouse AD models, with observed, distinct changes in synaptic‐ and immune‐associated genes in multiple brain regions. Activation of immune genes was highest in the brain stem, where detection of HSV‐1 was highest. The greatest changes in gene expression occurred at 7 months, with fewer changes following at 10 months. These changes are most similar to changes in early disease and support the role of HSV‐1 contributing to AD pathophysiology.