bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of Tau as a self‐antigen that drives T cell immunity in a tauopathy mouse model
Authors: Hu Hao , Ulrich Jason D , Holtzman David M. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the aggregation and accumulation of proteins including amyloid‐β and tau. We previously compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and found that mice with tauopathy but not amyloid developed a unique adaptive immune response with markedly increased activated T cells in areas with tau pathology. T cell depletion blocked tau‐mediated neurodegeneration. These indicate a pathogenic role for T cells in tau‐mediated neurodegeneration. Which antigens are presented to and activate T cells during tauopathy is unknown. Individuals developing AD pathology displayed increased tau species including with microtubule binding region (MTBR) in the extracellular space of CNS, which is rare in healthy individuals. These regions can be potentially recognized by T cells and lead to their activation. Also, neoepitopes can be generated from tau caused by the formation of neurofibrillary tangles, which contain tau hyperphosphorylation, acetylation, citrullination, ubiquitination. These may trigger an “allogeneic” T cell response. Thus, we hypothesize that tau could be a potential antigen that drives an autoimmune‐like response during development of tau pathology in a tauopathy mouse model.MethodWe intend to make use of an online epitope prediction tool ([https://www.iedb.org/]) to select candidate peptides derived from tau and test their immunological response by immunizing the mice with synthetic peptides. We will also utilize an unbiased TCR (T cell receptor) enrichment analysis to generate antigen (tau)‐specific T cells and test their pathological role during tau pathology.ResultIn our preliminary experiments, we successfully predicted multiple antigenic epitopes to MHC‐I or MHC‐II derived from full‐length human P301S tau mutant protein. We found several tau peptides from the top‐ranking predicted sequences can elicit a robust T‐cell response in P301S mice. We also generated T‐cell hybridomas that specifically recognize tau:225‐240 peptides.ConclusionTau‐specific T cells can develop in P301S mice. Completion of this project will attempt to provide a detailed immunological mechanism of how T cells become activated during tau pathology in AD. It will also provide new approaches to target these T cells or engineer therapeutic T cells to develop methods to treat tauopathies including AD.
Microglial deletion of C1q reduces phagocytosis of amyloid and synapses in an AD mouse model
Authors: Petrisko Tiffany J , Chu Shu‐Hui , Tenner Andrea J 
Published: January 2025

AbstractBackgroundThe complement system contributes to enhanced inflammation and cognitive decline in Alzheimer’s disease (AD). Previous studies have demonstrated constitutive deletion of the classical initiator protein, C1q, reduces glial activity and attenuates neuronal loss in AD mouse models. As it is now known that microglia are the primary producers of C1q in the brain, the objective of this study was to determine if microglial specific deletion of C1q would reduce lysosome associated phagocytosis of Vglut1, an excitatory synapse marker, and if reductions in the phagocytosis of Vglut1 would be accompanied by a reduction in the phagocytosis of beta‐amyloid.MethodBriefly, C1qaFL/FLCX3CR1Cre (designated C1qΔMG) mice, which show deletion of microglial C1q by 2 months of age, were crossed to ArcticC1qaFL/FL mice to generate WT and Arctic (Arc) C1qaFL/FL mice with and without the CX3CR1Cre transgene. Brains were then collected at 10m of age to study amyloid phagocytosis by microglia and astrocytes as well as microglial phagocytosis of Vglut1 using immunofluorescence. Briefly, sections were co‐labeled for microglia (Iba1) or astrocytes (GFAP), lysosomes (CD68 or Lamp2), and amyloid (6E10) or Vglut1. Confocal z‐stacks of amyloid plaques throughout the hippocampus were acquired at 40X using a 3.0 Zoom while microglia were imaged at 63X with a 3.5 Zoom in the CA1 subregion of the hippocampus.ResultsMicroglial engulfment (Iba1/6E10 co‐localization) and lysosome associated phagocytosis (Iba1/6E10/CD68) was significantly impaired in Arctic mice lacking C1q (p<0.05). While astrocytes did not change their engulfment of amyloid (GFAP/6E10 colocalization), lysosome associated phagocytosis of amyloid was significantly impaired in Arc C1qΔMG astrocytes. Arctic mice displayed increased phagocytosis of Vglut1 by microglia as expected, and the deletion of C1q from microglia significantly decreased this engulfment. Unexpectedly, WT C1qΔMG displayed increased Vglut1 phagocytosis compared to WT controls. No changes were observed in the percentage of Vglut1 puncta.ConclusionLoss of microglial C1q reduces amyloid uptake by astrocyte and microglia and in the CA1 region, lack of microglial C1q also reduces Vglut1 association with the lysosomes in the Arctic AD mouse model.
Neuropsychiatric symptoms are related to CSF amyloid and tau in individuals with subjective cognitive decline and mild cognitive impairment
Authors: Gonçalves Rochetti Ana Luiza , Ribeiro Isadora Cristina , Aventurato Ítalo Karmann , da SIlva Marjorie Cristina Rocha , Gonçalves Brenda Costa , Rizzi Liara , Balthazar Marcio Luiz Figueredo 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder that has become increasingly prevalent around the world and can be characterized in vivo by amyloid‐beta peptide and hyperphosphorylated tau protein. Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are potential previous stages of AD dementia. Behavioral and psychological symptoms are common in SCD and MCI, but their biological basis is still not clarified. This study aims to investigate the potential correlations between neuropsychiatric symptoms and AD biomarkers in patients with SCD and MCI.Methods71 subjects were recruited for a medical and psychological evaluation in the Clinical Research Center of UNICAMP, Brazil. They were diagnosed according to NIA‐AA criteria and underwent neuropsychiatric scales, including the Mild Behavioral Impairment Checklist (MBI‐C), a helpful questionnaire to measure behavioral and neuropsychiatric symptoms in the AD continuum. The subjects also underwent CSF collection to measure the biomarkers in the samples using immunoassay kits. We used Pearson correlation for the statistical analyses.ResultsWe found statistically relevant correlations between the MBI‐C C domain and the CSF amyloid‐beta (p = 0.026, r = ‐0.302, n = 54) and a correlation between the MBI‐C E domain and the CSF total‐tau protein (p = 0.026, r = 0.295, n = 57).ConclusionsThe MBI‐C C domain approaches symptoms of impulse dyscontrol, and the MBI‐C E domain comes with symptoms of abnormal perception or thought content. We found that psychological symptoms imply an association of these symptoms with the neurodegenerative process due to the correlation with total‐tau protein, a more specific biomarker.
Childhood adversity predicts worse verbal and visual memory in cognitively intact older White and Latino adults in California
Authors: Tucker Miwa , Watson Caitlin Wei‐Ming , Diaz Valentina E. , Aguirre Gloria A , Puac Jorge Achila , Martinez Luis E , Rodriguez Anne‐Marie , Archila Oscar Robles , Windon Charles , Jackson Ashley J. , Pina‐Escudero Stefanie D , Kramer Joel H. , Lanata Serggio 
Published: January 2025

AbstractBackgroundEmerging research suggests adverse childhood experiences (ACEs) have long‐lasting impacts on adult brain health, but few studies investigate these effects in older adults. The present study examined ACEs and their relationships to late‐life cognitive and mental health among older adults living in the San Francisco Bay Area.Method102 cognitively unimpaired older adults [mean age = 75, 58% female, 75% White, 25% Latino, mean education = 17 years] were enrolled in UC San Francisco’s Alzheimer’s Disease Research Center. Participants completed cognitive measures, the geriatric depression scale, and an ACEs survey (threat ACEs: e.g., abuse, discrimination; deprivation ACEs: e.g., unmet food or healthcare needs, neglect). Kruskal‐Wallis tests examined ACEs by sex and ethnicity. Linear regression models examined the effects of threat and deprivation ACEs on cognitive function and depression symptoms controlling for age, sex, and ethnicity. Sex and ethnicity were examined as potential moderators of these relationships.ResultOn average, older adults reported 2.6 threat ACEs (range = 0‐12) and 0.8 deprivation ACEs (range = 0‐6). Females and males reported similar levels of ACEs. Latinos endorsed significantly more threat ACEs (2(1) = 6.0, p = 0.01) and deprivation ACEs (2(1) = 6.6, p = 0.01) compared to Whites. Older adults who reported more deprivation ACEs performed significantly worse on verbal memory (β = ‐0.30; p = 0.006) and visual memory tasks (β = ‐0.26, p = 0.04) while controlling for age, sex, and ethnicity. No significant relationships were observed between deprivation and executive functioning, object naming, visual‐spatial construction, or depression symptoms (ps>0.50), nor between threat ACEs and any outcome (ps>0.10). Sex and ethnicity did not moderate relationships between ACEs and cognitive and mental health outcomes.ConclusionOur results suggest that deprivation ACEs may negatively and selectively impact the domain of memory among cognitively unimpaired older adults. Given episodic memory deficits are an early symptom of Alzheimer’s disease, this lowered memory function may increase dementia risk. Together, these findings suggest that early life interventions to support the basic needs of children could potentially reduce memory problems in late life. In future studies, cultural differences in the presentation and impacts of ACEs on late‐life cognitive and mental health should be examined to inform culturally adaptive interventions to support brain health.
Network Structure of depressive symptomatology in elderly with Cognitive Impairment
Authors: Pyo Jee Hyung 
Published: January 2025

AbstractBackgroundCognitive impairment and loss of concentration often resides in both depressive disorder and cognitive dysfunction such as Alzheimer’s dementia and mild cognitive impairment (MCI). Also, substantial population of cognitive dysfunction experience depressive symptoms. This study finds out network structure of items of geriatric depression scale (GDS) in patients with cognitive dysfunction.MethodThe sample of 5354 patients with cognitive dysfunction including both Alzheimer’s dementia [n = 1889], and MCI [n = 3464], were measured with GDS, geriatric depression scale, the extent of depressive symptoms. The scale is self‐administered questionnaire, which measures depression. Using exploratory graph analysis, network structure was analyzed as nodes and edges and centrality was represented as strength, betweenness, and closeness. The analysis was conducted between the subgroups of AD and MCI and evaluated by network comparison tests.ResultThe centrality indices found that the most central item of GDS was the item 12 “worthlessness” in patients with cognitive impairment. Subgroup analysis showed the worthlessness was most central in GDS among AD patients while emptiness was the most central in MCI patients.ConclusionThe preventive approach and early intervention for worthlessness might be a crucial point in depressive symptoms in patients with cognitive dysfunction.
Correlation between anticholinergic burden and behavioral and psychological symptoms in patients with cognitive impairment and dementia
Authors: Pistorio Sabrina , di Tella Gianluca Scotto , Merenda Raffaella , Bencivenga Leonardo , Zanetti Michela , Rengo Giuseppe , Femminella Grazia Daniela 
Published: January 2025

AbstractBackgroundDrugs with anticholinergic properties are frequently prescribed to patients with cognitive impairment. The cholinergic system plays an important role in the learning process, memory, but also in the regulation of emotions. The aim of this research is to investigate a possible correlation between the use of anticholinergic drugs and the risk of developing more severe behavioral and psychological symptoms (BPSD).MethodPatients with a diagnosis of subjective cognitive impairment, MCI or dementia were recruited from the Geriatric Unit of the AOU Federico II of Naples. Screening tests for cognitive impairment (MMSE, ACE‐R) and functional status (ADL, IADL) were performed. BPSD were evaluated with the Neuropsychiatric Inventory (NPI). The anticholinergic burden was calculated using the ACB calculator. We compared patients at low risk of anticholinergic adverse effects (ACB<3) versus patients at high risk (ACB≥3). Chi‐square test and Mann‐Whitney test were used to compare the two groups. A multiple linear regression was performed to identify factors associated with a higher NPI score. A p value <0.05 was considered statistically significant.ResultA total of 173 patients (mean age 74±7, 74 men) were included in the study; 132 patients with ACB<3 (low risk) versus 41 patients with ACB ≥3 (high risk) were compared. No statistically significant differences were found between the two groups in terms of demographics (age, sex) and anamnestic variables (education, marital status, family history of dementia, hypertension, diabetes, smoking, dyslipidemia, atrial fibrillation, coronary heart disease, use of alcohol and polypharmacy). Significantly higher NPI scores were found in patients with ACB≥3 (median scores 48.0 vs 15.5, p = 0.00). Furthermore, patients with ACB≥3 showed lower MMSE (median scores 19.0 vs 24.5, p = 0.00) and more IADLs lost. In the multivariate regression analysis, after adjusting for age, sex, polypharmacy and IADLs lost, only the MMSE scores and the ACB score were independent predictors of the NPI score.ConclusionIn conclusion, the anticholinergic burden might play a role as a risk factor for developing more severe BPSD in patients with subjective cognitive impairment, MCI and dementia, independently of the degree of cognitive impairment.
In Situ Proximity Proteomics in Post‐Mortem Human Brain Tissue Uncovers Differences Tau Lesion Proteomes Between Tauopathies
Authors: Morderer Dmytro , Wren Melissa C , Liu Feilin , Kouri Naomi , Maistrenko Anastasiia , Khalil Bilal , Lee Jannifer H , Salemi Michelle , Phinney Brett , Dickson Dennis W. , Murray Melissa E. , Rossoll Wilfried 
Published: January 2025

AbstractBackgroundNeuropathologic inclusions formed by hyperphosphorylated protein tau in the brain are a hallmark of Alzheimer’s disease and other human neurodegenerative disorders commonly referred to as tauopathies. Tau lesions differ in their disease‐specific morphological presentations, affected cell type, subcellular compartments and tau isoforms present in the inclusions. In addition, tau filaments isolated from different tauopathies have distinct fibrillar structures that potentially underlie the morphological diversity of tau lesions. The factors that govern the formation of disease‐specific tau lesions and distinct patterns of neurodegeneration and clinical presentations are unknown. To address this gap of knowledge, we performed profiling of proteomes associated with phospho‐tau aggregates in 4 major tauopathies.MethodWe utilized the in‐house developed Probe‐dependent Proximity Profiling (ProPPr) method combined with data‐independent acquisition mass spectrometry to profile phospho‐tau associate proteomes in formalin‐fixed paraffin‐embedded (FFPE) frontal cortex tissue sections from the Mayo Clinic Florida Brain Bank. Selected candidates were validated by fluorescent co‐immunostaining of patient brains with corresponding antibodies.ResultIn situ proximity proteomic profiling revealed over 1300 protein associated with phospho‐tau pathology, including 229 proteins that were identified in all tauopathies. The most significantly enriched GO terms in this protein set common to all the tauopathies were related to chaperone activity, guanyl nucleotide binding, cadherin binding, cytoskeleton, and ion transporter activity, highlighting biological processes and pathways affected by tau aggregation regardless of the type of tau lesion. In addition, we identified 32 proteins with significantly different association with phospho‐tau between tauopathies. Immunostaining of post‐mortem patient frontal cortices confirmed some of the findings from proteomics and revealed differences in abundance and localization patterns of several tau‐associated proteins between tauopathies, uncovering a potential of using these proteins as biomarkers for antemortem diagnosis.ConclusionTau lesions in different tauopathies have differences in their associated proteomes that can be assessed by the ProPPr assay.
Multi‐omic approaches to defining disease heterogeneity, subtypes, and progression
Authors: Bennett David A. 
Published: January 2025

AbstractBackgroundThe aging and dementia field has long been interested in understanding disease heterogeneity, subtypes, and progression. Work has progressed from clinical, to neuroimaging to biomedical devices to neuropathological data, and now brain and blood omic data.MethodThe AMP‐AD consortium generated and/or annotated genomic, epigenomic, transcriptomic, proteomic, and metabolomic data from brain and/or blood from thousands of study participants and patients across the 8 teams. They include women, men, non‐Latino white and black, and Latinos, covering the full spectrum of clinical and neuropathologic traits and diseases. All data were deposited in the AD Knowlege Portal (www.synapse.org) and made available to the wider aging and dementia research community in an open science environment.ResultThe omic data has been leveraged by members of the AMP‐AD teams, the SAGE bionetworks team which manages the Portal, and the wider research community to address disease heterogeneity, subtypes, and progression at the molecular level. New computation tools and approaches were developed and/or adapted from the cancer space as such deep and varied brain omic data were not previously available from humans. Initial studies used a single layer of data. Later studies integrated two or more layers of data. Ongoing work is now bridging the gap to project blood omic data to molecular trajectories in the same humans. Examples of the work across this spectrum will be presented.ConclusionThe data generated and/or annotated in first decade of AMP‐AD is now defining disease heterogeneity, subtypes, and progression at the molecular level in the brain and beginning to bridge the gap to data obtainable from living humans. It is hoped that this will move the field closer to a time when precision medicine for brain diseases can target brain molecular pathways.
Ten year anniversary of AMP AD: Enabling a Precision Medicine Approach to Target and Biomarker Discovery for Alzheimer’s Disease
Authors: Ertekin‐Taner Nilüfer , Petanceska Suzana S 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is complex and multifactorial. Precision medicine approaches are needed to capture the basis of heterogeneity in AD pathogenesis, clinical presentation and neuropathology. Large‐scale molecular, deep phenotypic and exposomal data necessary to enable precision medicine research requires team‐based, interdisciplinary programs. Accelerating Medicines Partnership in Alzheimer’s Disease (AMP‐AD) was launched in 2014 with the goals to characterize disease heterogeneity and discover precision‐medicine therapeutic targets and biomarkers for AD and related disorders (ADRD).MethodAMP‐AD consortium, comprising eight teams addresses the barriers that historically limited therapeutic target and biomarker discovery in ADRD by characterizing the molecular disease complexity in deeply phenotyped human biospecimens and experimental disease models. Over the past decade, AMP‐AD teams generated multi‐omics data in ∼2,000 human brain samples from largely non‐Hispanic white donors and from >600 African American and Latin American donors. AMP‐AD datasets, including bulk and single cell molecular profiles from brain and peripheral tissues are analyzed using innovative analytic approaches generated and applied by these teams. Findings are validated with a broad array of cross‐species experimental platforms including human iPSC, fly and rodent models. These outcomes are integrated with deep phenotypic and exposomal measures for precision medicine discoveries and broadly shared.ResultAMP‐AD generates high‐dimensional molecular data and applies novel systems biology approaches bringing new insights into ADRD. AMP‐AD teams discovered molecular subtypes of AD and characterized the cell‐type specificity of these molecular changes. Discovery of disease signatures in brain and peripheral tissues enabled nominations of precision medicine therapeutic targets and biomarkers. Over 600 targets, annotated with human and cross‐species data, are shared with the research community on the Agora Platform of AD Knowledge portal that also houses all research data and outputs for rapid and responsible dissemination in a centralized manner.ConclusionFirst decade of AMP‐AD led to unprecedented data and knowledge for rigorous and reproducible ADRD research, accelerated the delivery of many new disease insights, and expanded the target and biomarker landscape. Future directions include discovery of subtypes for disease specificity and progression, contextualized by multi‐ethnic, molecular, exposomal data and validation platforms well‐integrated into therapeutic development pipelines to deliver new cures to ADRD.
The role of immunoproteasomes in modulating neuro‐inflammation in Alzheimer’s Disease
Authors: Kumar Mayank , Jiang Shan , Lorman Daniella , David Larr , Soni Rajesh , Kissner Michael , Yang Mu , Myeku Natura 
Published: January 2025

AbstractBackgroundThe immunoproteasome (IP) is the inducible form of the constitutive 20S proteasome upregulated in immune cells. The IP consists of 3 inducible β subunits (β1i – LMP2, β2i – MECL1, and β5i – LMP7), which generate MHC‐I compatible peptides. IPs are induced by pro‐inflammatory cytokine signaling, as well as oxidative stress signaling. Furthermore, in AD, the presence of aβ results in induction of IP in glial cells like microglia and astrocytes. The evidence for the induction of IPs in Alzheimer’s Disease (AD) pathology is numerous and unequivocal; however, the mechanism of induction of IPs in AD is still unclear. Accordingly, this study adds evidence to answer the question of whether IPs are induced as a compensatory mechanism for restoring homeostasis in AD or are induced due to the vicious cycle of inflammation and add to its pathological consequences.MethodThe mice used in the study were genetically modified from a C57/BL6J background to obtain an AD model. This was achieved by knock‐in (KI) of Amyloid Precursor Protein (APPNL‐G‐F/NL‐G‐F) gene, and human MAPT (hTau+/+) gene. Furthermore, to obtain IP deficient mice, the KI mice had the lmp7‐/‐ (βi5) and mecl‐/‐ (βi2) genes knocked out.Quantitative analysis of confocal images was performed for AD progression and gliosis levels (n = 4). This was correlated with functional changes of Affective and Cognitive behaviors (n = 10). To observe changes in immune response and neuro‐inflammation, multi‐color FACS (n = 3), subsequent bulk RNA sequencing (n = 3), along with snRNAseq (n = 3) was performed for microglia, lymphocytes, and astrocytes. In addition, multiplex cytokine assay (n = 3) was performed for gauging the neuro‐inflammation along with proteomics of CSF (n = 6), and immunopeptidomes (n = 3) of MHC‐I &II peptides by Mass Spectrometry.ResultIt was observed that IP deficiency caused a distinct change in microglial and astrocytic phenotypes and an increased infiltration of lymphocytes. This was seen to increase pro‐inflammatory cytokines in IP deficient mice with a decrease in novel MHC associated immune peptides.ConclusionIt can be concluded that IP deficiency causes increased inflammation, gliosis, and consequent progression of AD.