bluuebunny/crossref_metadata_2025 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

Background

Alzheimer’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.

Method

We 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.

Result

In 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.

Conclusion

Tau‐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

Background

The 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.

Method

Briefly, 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.

Results

Microglial 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.

Conclusion

Loss 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

Background

Alzheimer’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.

Methods

71 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.

Results

We 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).

Conclusions

The 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

Background

Emerging 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.

Method

102 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.

Result

On 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.

Conclusion

Our 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

Background

Cognitive 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.

Method

The 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.

Result

The 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.

Conclusion

The 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

Background

Drugs 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).

Method

Patients 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.

Result

A 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.

Conclusion

In 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

Background

Neuropathologic 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.

Method

We 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.

Result

In 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.

Conclusion

Tau 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

Background

The 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.

Method

The 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.

Result

The 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.

Conclusion

The 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

Background

Alzheimer’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).

Method

AMP‐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.

Result

AMP‐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.

Conclusion

First 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

Background

The 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.

Method

The 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.

Result

It 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.

Conclusion

It can be concluded that IP deficiency causes increased inflammation, gliosis, and consequent progression of AD.
Tau pathology induced alteration in neuronal activity disrupt sleep and cerebral metabolic rhythms in the P301S PS19 mouse model of tauopathy
Authors: Irmen Riley E , Carroll Caitlin M , Constnantino Nicholas J , Snipes James A , Macauley Shannon L
Published: January 2025

Background

Alzheimer’s disease is defined by the pathological aggregation of amyloid‐beta and hyperphosphorylated tau. AD patients often exhibit other symptoms like metabolic and sleep dysfunction. Currently, it is unclear if impairments are a cause or consequence of Aβ or tau aggregation. Previously, we demonstrated cerebral and peripheral changes in glucose elevate brain lactate levels stimulating wake. Further, previous work showed tau pathology corresponds with decreased sleep. Currently, it’s unclear what mechanisms drive sleep changes or if it relates to metabolic dysfunction. Therefore, we investigated how tau pathology impacts sleep and metabolism in P301S mice.

Methods

To examine peripheral metabolism, glucose tolerance tests were conducted on P301S and wild‐type mice(female). Recordings of indirect calorimetry over 3 days further explored peripheral metabolism. Paired glucose and lactate biosensors in the hippocampi tracked sub‐second fluctuations of brain interstitial fluid (ISF) to observe cerebral metabolic changes. EEG and EMG recorded cortical activity over a 3‐day period and spectral analysis investigated sleep/wake architecture.

Result

Tau aggregation preserves peripheral glucose tolerance and diurnal rhythms of brain glucose/lactate, normally lost in aged controls, suggesting increased glucose utilization. Similarly, P301S mice show increased respiratory exchange ratio suggesting heightened carbohydrate utilization. Conversely, they exhibit diminished energy expenditure. EEG spectral analysis revealed increased delta, increased theta, and decreased beta with pathology, suggesting disrupted GABA activity and sleep drive. Starting early in pathology, mice display increased wake and decreased NREM/REM. Effects on total sleep depend heavily on decreased REM bout number and duration.

Conclusion

Blood glucose levels in P301S mice fail to rise in response to glucose injection. Brain glucose/lactate fluctuations are maintained suggesting tau pathology preserves glucose utilization. Conversely, decreased NREM and REM and increased wake were exhibited with tau pathology. EEG spectral analysis indicates decreased beta activity, suggesting diminished GABA activity. Increased theta during NREM suggests increased pressure to transition to REM sleep. Reduced sleep drive is illustrated by increased delta in wake. Together, tau pathology reduces sleep drive and ability to switch between vigilant states despite increased sleep need. These results suggest that tau pathology causes excitatory/inhibitory imbalance and sleep impairment but does not contribute to profound effects on cerebral metabolic rhythms.
The role of TGFbeta signals in Lead (Pb)‐induced Cerebral Amyloid Angiopathy
Authors: Gu Huiying , Luo Alexandria , Zheng Wei , Du Yansheng
Published: January 2025

Background

Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) results in longitudinal decline in cognitive function and brain atrophy. In animals, chronic Pb exposure can increase brain Aβ deposition. However, it remains unclear how Pb induces different natures of amyloid depositions and underlying mechanisms to contribute to the pathogenesis of AD and related dementia.

Method

Female APP/PS1 mice at 8 weeks old were administered with either 50 mg/kg Pb‐acetate (PbAc) (i.e., 27 mg Pb/kg) via oral gavage or an equivalent molar concentration of Na‐acetate (NaAc) once daily for additional 3 days or 8 weeks, in the presence or absence of an PAI‐1 inhibitor (12mg/kg). Parenchymal plaques and vascular amyloid deposition were quantitated by double staining with Thioflavin S and anti‐collagen IV antibody. Brain sections were also stained with anti‐NeuN (for neurons), anti‐myelin basic protein (for myelination) and anti‐rabbit FITC (for reactive astrocytes) antibodies. Assays for perivascular drainage as well as in vitro vascular binding with Aβ and microglial endocytosis were also performed.

Result

2‐month Pb exposure increased vascular Aβ deposits in neocortex of female APP/PS1 mice at the 4‐month of age by almost 300% (p<0.01). In contrast, Pb only increased parenchymal amyloid in the same brain areas by 86.7% (p<0.05). Demyelination, but not neuronal loss was observed in Pb‐treated AD mice that had significantly cognitive deficits detected by Y‐maze. Following Pb treatments, the ratios of Aβ1‐40/Aβ1‐42 in Pb‐treated groups increased to 0.58 ± 0.21 in the cortical parenchyma and 0.50 ± 0.10 in the brain vasculature, as compared to those in the control group (0.39 ± 0.09 and 0.11 ± 0.02). Additionally, TGF‐β1, Smad2, PAI‐1 and fibronectin were significantly induced in cerebrovasculature isolated from mice treated with 27 mg/kg of Pb for 3 days, accompanied by dramatic inhibition of perivascular drainage and vascular binding with Aβ1‐40. Furthermore, Pb exposure induced microglial TGF‐β1 and inhibited clearance of Aβ40 and LRP‐1 expression. Interestingly enough, all of these alterations induced by Pb exposure could be markedly ameliorated by a PAI‐1 inhibitor.

Conclusion

TGF‐β signals play distinct roles in Pb‐induced amyloid pathology.
Brain arteriolosclerosis is linked to lower gray matter volume in community‐based older adults
Authors: Tomash Ana , Tazwar Mahir , Yasar Md Tahmid , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: January 2025

Background

Brain arteriolosclerosis is characterized by the thickening of vessel walls and arteriolar stenosis and is one of the primary pathologies of cerebral small vessel disease. Arteriolosclerosis is linked to lower cognitive and motor function, as well as an elevated risk of dementia. This study aimed to investigate the association of brain arteriolosclerosis with regional gray matter volumes in a large number of community‐based older adults.

Method

Data from ex‐vivo MRI and detailed neuropathological evaluation were collected from older adults (N = 882) participating in four longitudinal, clinical‐pathologic cohort studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig. 1A). Cerebral hemispheres from all participants were obtained at autopsy and imaged ex‐vivo with a multi‐echo spin‐echo sequence (ME‐SE) on 3T clinical MRI scanners approximately one month postmortem. The acquired voxel size was 0.6mm × 0.6mm × 1.5mm, and the scan time was approximately 30 minutes. The gray and white matter were segmented in the ex‐vivo MRI data. Subsequently, the gray matter underwent further division into 42 cortical and subcortical regions using multi‐atlas segmentation. The volume of each region was measured and normalized by the participant’s cerebral hemisphere volume. Following ex‐vivo MRI, a detailed neuropathologic assessment was performed on pathologies including arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts, Alzheimer’s pathology, Lewy bodies, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), and hippocampal sclerosis (Fig. 1B). For statistical analysis, linear regression was employed to explore the association of brain arteriolosclerosis with regional gray matter volumes (normalized by cerebral hemisphere volume) controlling for all other neuropathologies (Fig. 1B), demographics (age at death, sex, years of education), postmortem intervals, and scanner (Fig. 1A).

Result

More severe brain arteriolosclerosis was associated with lower volume in several gray matter regions, including medial orbitofrontal, superior frontal, pericalcarine, cuneus, and lateral occipital areas, independently of the effects of other neuropathologies (Figs. 2, 3).

Conclusion

This study demonstrated that brain arteriolosclerosis is associated with lower volume in multiple gray matter regions independently of the effects of other vascular or neurodegenerative pathologies.
GWAS of neuropsychiatric symptoms in Mild Cognitive Impairment and Alzheimer’s Disease/Related Disorders
Authors: Wingo Aliza P. , Vattathil Selina M. , Wingo Thomas S.
Published: January 2025

Background

Approximately 85% of individuals living with MCI or ADRD experience one or more neuropsychiatric symptoms (NPS), referred to as ADRD‐NPS. They include depression, anxiety, irritability, apathy, agitation, delusions, hallucinations, and sleep disturbances. ADRD‐NPS are associated with greater functional impairment, higher caregiver burden, and earlier institutionalization. However, we have limited insight into mechanisms underlying ADRD‐NPS to develop effective treatments. Here, we conducted a GWAS of ADRD‐NPS to investigate genetic loci contributing to ADRD‐NPS.

Method

We included only participants with MCI or ADRD in the GWAS of ADRD‐NPS. A total of 12,728 participants of European ancestry recruited by the U.S. Alzheimer’s Disease Research Centers were included. Among them, 23% had MCI and 77% had ADRD. ADRD‐NPS were assessed with the NPI‐Q. We conducted a GWAS for each of the ADRD‐NPS domains. Additionally, we performed a multivariate GWAS of all ADRD‐NPS domains simultaneously using a linear mixed model.

Result

Both the GWAS of anxiety and the GWAS of delusion identified several genome‐wide significant SNPs (p < 5 × 10‐8) located in a 41 Kb region of chr19q13.32 after adjusting for sex, MCI/ADRD status, genotyping batch, and 10 PCs. Since this region overlaps the APOE gene and thus these signals may be related to severity of cognitive impairment (MCI or ADRD), we performed a stratified GWAS in MCI and ADRD separately. The stratified GWAS found that some of these signals remained genome‐wide significant in ADRD participants (n = 9766) for both anxiety and delusion, respectively. Furthermore, we found that APOE e4 allele was strongly associated with ADRD‐NPS in the domain of anxiety (p = 1.9 × 10‐10), hallucinations (p = 1.6 × 10‐5) and delusions (p = 4.0 × 10‐12) after adjusting for sex, MCI/ADRD status, genotyping batch, and 10 PCs. Lastly, the multivariate GWAS of ADRD‐NPS identified genome‐wide significant SNPs on chromosome 14 (KIF26A) and 19 (APOE) after adjusting for sex, MCI/ADRD status, genotyping batch, and 10 PCs.

Conclusion

APOE e4 and genetic variants in chr19q13.32 are associated with anxiety and delusion experienced by individuals with MCI or ADRD. We plan to integrate the GWAS findings with human brain proteomic data to identify brain proteins contributing to ADRD‐NPS to nominate targets for therapeutic investigation.
Senescent cells, a promising target for Alzheimer's Disease
Authors: Guerrero Ana
Published: January 2025

Background

Senescence is a cellular response to stress or damage leading to a state of irreversible growth arrest. As we age, the number of senescent cells increases and directly contributes to age‐related conditions including cancer and neurodegenerative diseases. As a result, there is a growing interest to therapeutically target senescence either with drugs eliminating senescent cells (senolytics) or with strategies to modulate their secretory phenotype among others. Importantly, even though the accumulation of senescent cells is a key hallmark of ageing, and ageing the biggest risk factor for Alzheimer´s Disease (AD), the extent of senescence in the brain during AD remains elusive.

Method

We have developed a new preclinical model combining a mouse model of amyloid pathology (App NL‐G‐F knock‐in) with both a senescence transgenic reporter and a conditional targeted cell ablation lines based on p16Ink4a expression, a well‐known senescence marker. This model allows to track the onset of cellular senescence in response to amyloid deposits and to evaluate the therapeutic potential of the selective elimination of senescent cells.

Result

In this Presentation, I will give an overview on the available strategies to therapeutically target senescence and share some preliminary data obtained with our new preclinical model.

Conclusion

There is an urgent need to explore new therapeutic avenues to improve the lives of those affected by AD, either by delaying the onset and progression of the pathology, or by ameliorating the symptoms of this devastating disease. Cellular senescence constitutes a promising target that warrants further investigation.
Defects in the signaling lipid PI3P may contribute to dendritic spine loss in Alzheimer’s disease
Authors: Rivero‐Rios Pilar , Uygun Tunahan , Chavis Garrett D. , Sutton Michael A. , Weisman Lois S.
Published: January 2025

Background

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. The recent announcement that lecanemab, a monoclonal antibody targeting amyloid‐b, can slow down cognitive decline in AD is a great step forward in the battle against the disease. However, the modest success achieved in the clinical trial speak to the need for developing additional pharmaceutical approaches to target other key features of AD. Notably, dendritic spine loss correlates more strongly to cognitive decline in AD than amyloid pathology, but the molecular causes remain poorly understood.

Method

We performed immufluorescence studies in cultured primary hippocampal neurons to evaluate endosomal defects and dendritic spine loss.

Result

We discovered that endocytic recycling of cell surface receptors from endosomes to the plasma membrane is key to maintain dendritic spine density in cultured hippocampal neurons. There are two major pathways for endocytic recycling: SNX27‐Retromer and SNX17‐Retriever. Our unpublished data show that both pathways contribute to dendritic spine maintenance by promoting the recycling of different sets of surface proteins at synapses. Moreover, alterations in either pathway result in a loss of dendritic spines.

In addition, we found that the recruitment of SNX17 and SNX27 to synapses is dependent on the signaling lipid phosphatidylinositol‐3‐phosphate (PI3P). Notably, a lipidomic study revealed that PI3P levels are decreased in postmortem brain tissue from AD patients as well as in AD‐related mouse models. Thus, the observed decrease in PI3P levels may contribute to spine loss in AD and act in part by dysregulating endocytic recycling at synapses.

Conclusion

Continued studies of the connections between PI3P, spine density and AD may ultimately open avenues for new therapeutic approaches for this devastating disease.
Harbingers of Disease: Decoding Shared Multi‐Omic Changes in Human and Mouse Models of Alzheimer’s Disease
Authors: Swarup Vivek , Morabito Samuel , Miyoshi Emily , Head Elizabeth , Green Kim N.
Published: January 2025

Background

Alzheimer’s Disease (AD) presents a significant challenge in understanding its complex pathophysiology, owing to its multifaceted genetic and environmental factors. Despite extensive research, the translatability of findings from animal models to human conditions remains a critical hurdle. This study addresses the need to uncover shared molecular changes in AD by comparing human and mouse models, thereby enhancing our understanding of the disease’s underlying mechanisms and improving the prospects for effective treatments.

Method

The study employed a comprehensive multi‐omic approach, integrating spatial transcriptomics (ST) and single‐nucleus RNA‐sequencing (snRNA‐seq) data from postmortem human prefrontal cortical tissue and 5xFAD mouse brains across various stages of AD pathology, including AD in Down Syndrome (DS). An unbiased clustering algorithm, BayesSpace, was used to identify distinct clusters in both human and mouse datasets. Cross‐species differential expression analysis and multi‐scale co‐expression network analysis using hdWGCNA were conducted. These analyses were complemented with fluorescent amyloid imaging to correlate gene expression changes with amyloid pathology.

Result

The analysis revealed evolutionary‐conserved AD transcriptional changes, particularly in genes associated with amyloid‐beta response and microglial activation. The study identified upregulated genes with age in the mouse model, with variances across different brain regions. Co‐expression network analysis exposed amyloid‐associated gene modules that were consistent across species. Additionally, the integration of spatial and single‐cell data elucidated cellular diversity and transcriptomic alterations within the AD brain, providing a spatial context to the observed molecular changes.

Conclusion

This study successfully decodes shared multi‐omic changes in human and mouse models of Alzheimer’s Disease, highlighting key molecular similarities and differences across species. The findings underscore the significance of a multi‐faceted, integrated omic approach in understanding AD pathogenesis. This cross‐species analysis not only advances our knowledge of the molecular underpinnings of AD but also opens avenues for developing more accurate and translatable AD models, ultimately guiding the discovery of potential therapeutic targets.
BIN1 regulation of brain region‐specific tau pathogenesis and propagation
Authors: Ponnusamy Moorthi , Wang Shuai , Yuksel Melike , Patel Om , Hansen Mitchell , Collier Lisa , Thinakaran Gopal
Published: January 2025

Background

BIN1, the second strongest GWAS risk factor for late‐onset Alzheimer’s disease (AD), encodes a nucleocytoplasmic adaptor protein that plays many roles in multiple tissue and cell types. It is known that BIN1 can directly bind to tau in vitro, and neuronal BIN1 expression decreases in patients with AD. Accumulation of intracellular hyperphosphorylated tau is a hallmark pathogenic feature of AD and related tauopathies. Neuronal BIN1 localizes to presynaptic terminals and influences excitatory synaptic transmission, however, the molecular events underpinning neuronal BIN1 function in disease progression in vivo has remained unclear.

Method

To mimic the decrease in neuronal BIN1 expression in Alzheimer’s patients, we recently generated and characterized tau pathology in novel conditional Bin1 knock‐out (tau P301S transgenic mice lacking BIN1 expression in the forebrain excitatory neurons; PS19:Bin1‐cKO) and examined tau pathogenesis. In order to establish a direct connection between neuronal BIN1 and the degree of neurofibrillary tangle pathology, we injected tau seeds into the brains of PS19:Bin1‐cKO mice and investigated tau propagation and spreading.

Results

We observed that the loss of excitatory neuronal BIN1 expression attenuates tau accumulation and neurodegeneration selectively in the hippocampus, entorhinal/piriform cortex, and amygdala. Furthermore, the knock‐out mice had significantly reduced neuroinflammation, preservation of hippocampal synapses, and complex transcriptomic changes in the neurons and glial cells. In addition, we observed reduced brain‐derived tau seed propagation from the site of injection in the hippocampus into connected cortical regions. Instead, there is an accumulation of Ser202/Thr205 phosphorylated tau and MC1+ tau in hippocampal CA1 pyramidal neurons. Thus, our findings reveal an interesting region‐specificity in neuronal BIN1 regulation of tau pathogenesis and propagation.

Conclusion

Overall, our findings reveal that excitatory neuronal BIN1 promotes region‐specific tau pathogenesis and tau propagation through neuroanatomically connected brain regions. These findings add to our understanding of in vivo BIN1 function in the context of tau pathogenesis, revealing cell‐autonomous and non‐cell‐autonomous mechanisms involved in BIN1 modulation of tau burden in AD.
Differential alterations of lateral entorhinal cortex impact on CA1 pyramidal neuron subpopulations in PS19 mouse model of tauopathy
Authors: Tian Chengju , Reyes Isabel , Thangavel Mohankumar , Masurkar Arjun V.
Published: January 2025

Background

The lateral entorhinal cortex (LEC), followed by area CA1 of hippocampus, are interconnected brain areas implicated early in Alzheimer’s disease (AD). Processing of LEC input by CA1 pyramidal neurons (PNs) is critical for non‐spatial memory, in which deficits are seen in early AD. How this process is affected by tauopathy is unclear. Furthermore, CA1 PNs are divided into molecularly and functionally distinct superficial (sPN) and deep (dPN) subpopulations. It is additionally unclear if and how LEC input processing by these subpopulations are differentially impacted.

Method

LEC of female PS19 and WT mice (8‐10 month old) were injected with an AAV expressing channelrhodopsin ChrR2. After two weeks, acute hippocampal slices were prepared and whole cell patch clamp recordings were performed on dPNs/sPNs of distal CA1 in current clamp and voltage clamp mode using a potassium‐ or cesium‐based intracellular solution, respectively. Synaptic responses were measured in current clamp and voltage clamp mode, with LEC axons optogenetically activated by blue LED light. In current clamp, excitatory postsynaptic potentials (EPSPs) were measured with inhibition blocked. In voltage clamp, excitatory postsynaptic currents (EPSCs) were evaluated by holding membrane potential at ‐70mV, and inhibitory postsynaptic currents (IPSCs) were evaluated by holding at 0mV.

Result

All data is n = 3‐8/group. Compared to WT, LEC‐driven EPSCs showed significant reductions in PS19 sPNs (18.7pA vs. 8.4pA, p = 0.0016) but were unchanged in dPNs (12.4pA vs. 13.6pA, p = 0.2841). Measurements of LEC‐driven EPSPs showed analogous findings. There was no change in paired pulse ratio, ruling out presynaptic changes. There was no change in EPSP decay time constant or temporal summation of the EPSP, ruling out changes in postsynaptic excitability. In contrast to excitation, LEC‐driven IPSCs were unchanged in PS19 versus WT mice in both sPNs (45.7pA vs. 51.9pA, p = 0.62) and dPNs (25.46pA vs. 22.3pA, p = 0.22).

Conclusion

LEC drive of CA1 PNs exhibits a cell type‐specific vulnerability to tauopathy, with sPNs differentially susceptible to a reduction of excitation, without changes in feedforward inhibition. Our results further support a postsynaptic mechanism that may be due to spine loss, changes in spine morphology, or shifts in glutamate receptor expression.