bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex dependent pleiotropic effects of Apolipoprotein (ApoE) 4 on executive function in mice and humans
Authors: Longmuir Madison , Arrar Aya , Onuska Kate M. , Spreng R. Nathan , Palmer Daniel , Bussey Timothy J , Saksida Lisa M , Prado Vania F , Prado Marco A.M. , Schmitz Taylor W. , Group PREVENT‐AD Research 
Published: January 2025

AbstractBackgroundApoE4 is the strongest genetic risk factor for late onset Alzheimer’s Disease (AD). However, ApoE4 has also been suggested to exhibit antagonistic pleiotropy, a phenomenon by which some allelic variations of a gene promote fitness during certain periods of life but may be detrimental in others. Previous work suggests that ApoE4 carriers exhibit superior performance on executive function tasks in early and middle age, while later in life (>70 years) ApoE4 carriers experience greater cognitive decline across multiple domains. We examined this ApoE4 antagonistic pleiotropy hypothesis using a cross‐species translational approach, focusing on cognitively unimpaired human adult ApoeE4 carriers and non‐carriers who were within a relatively younger age range (<70 years). We complement this using knock‐in mouse models that express humanized wild‐type App, MAPT, and ApoE3 or ApoE4 genes. To quantify executive function in both human and mouse, we used cross‐species touchscreen based Continuous Performance Task (CPT) to assess selective attention.MethodHuman participants were recruited from the PREVENT‐AD program at the Douglas Research Centre. Human touchscreen CPT testing was conducted using an MS SurfacePro. Mice were tested with the same task as humans using an operant chamber platform.ResultOur initial behavioural results suggest that ApoE4 facilitates attentional processes in both older adults and mouse ApoE4 carriers, as indexed by discrimination performance on the CPT. Further strengthening this translational pattern, we found that the facilitative effect of ApoE4 on CPT was more pronounced in female ApoE4 carriers of both species. In mice, we were able to examine this ApoE‐dependent effect on attention longitudinally. Consistent with antagonistic pleiotropy hypothesis, ApoE4 female mice present a higher CPT performance early in life (6‐9 months of age) when compared to ApoE3 mice, but this difference was reduced by 12 months of age.ConclusionTaken together, these results support the ApoE4 antagonistic pleiotropy hypothesis, whereby ApoE4 carriership confers greater attentional performance early in life in both female humans and mice. These new mouse models, in combination with fully translatable touchscreen tests of cognition, can be used to explore potential mechanisms by which ApoE4 can affect different aspects of brain function across the life span
Reduced microglia Trem‐2 expression promotes LPS‐induced AD‐like pathology
Authors: Bhat Shahnawaz A 
Published: January 2025

AbstractBackgroundFollowing the genome‐wide association studies (GWAS) discovery of microglia‐specific genes, particularly Trem‐2, SHIP‐1, and CD33, significantly associated with higher Alzheimer’s disease (AD) risk, the microglia TREM2 pathway has become central for regulating amyloid load, tissue damage, and limiting its spread. These discoveries have opened up the exciting possibility of therapeutic microglia TREM2 manipulation in AD. To date, however, several elements of TREM2 signaling remain unknown, ranging from the temporal activation pattern and receptor‐ligand binding to modulation of the brain microenvironment. This study aimed to investigate the consequences of reduced microglia Trem‐2 expression on oxidative stress, inflammatory response, and cognitive impairment. We hypothesized that a decrease in Trem‐2 expression would lead to an increase in oxidative stress markers, an up‐regulation of inflammatory cytokines, and a decline in cognitive functionMethodWe mimicked the neuroinflammatory milieu of AD by using LPS as a neuroinflammatory tool in vitro (BV2 microglia) and in vivo (C57BL6 mice).ResultWe found that LPS‐induced reduction in Trem‐2 expression resulted in significantly higher levels of oxidative stress markers, including increased production of reactive oxygen species (increased DCFDA intensity), nitrite level, and reduced GSH content, both in vitro and in vivo. Likewise, we observed a significant increase in the level of tumor necrosis factor‐alpha (TNF‐α) in both the BV2 microglia and C57BL6 mice following LPS treatment. Furthermore, the MWM cognitive test revealed a decline in spatial memory and learning abilities in mice with decreased Trem‐2 expression compared to control mice.ConclusionThese results emphasize the importance of Trem‐2 in maintaining a healthy brain environment and suggest that targeting Trem‐2 could be a potential therapeutic strategy for neurodegenerative diseases associated with microglia dysfunction.
Investigating the role of SORL1 in mediating AD‐specific endolysosomal phenotypes in neurons and microglia
Authors: DeRosa Brooke A. , Zhang Yalun , Golightly Charles G. , Coombs Lauren , Rothschild Lauren E. , Kunkle Brian W. , Cuccaro Michael L. , Vance Jeffery M. , Pericak‐Vance Margaret A , George‐Hyslop Peter St , Dykxhoorn Derek M. 
Published: January 2025

AbstractBackgroundDysregulation of endolysosomal trafficking is a major pathogenic mechanism in Alzheimer’s disease (AD). From the family of AD‐linked endosomal pathway genes, SORL1 stands out as one of the highest risk factors. SORL1 encodes an endocytic sorting receptor that mediates endosomal trafficking and processing of key AD‐associated molecules, including pathogenic forms of amyloid‐β (e.g., Aβ42) and amyloid precursor protein (APP). Using complementary cell‐based model systems, we investigated the role of a protein‐truncating SORL1 variant on endolysosomal trafficking and APP processing.MethodInduced pluripotent stem cell (iPSC) lines were derived from two siblings affected with early onset AD (EOAD) who carried a rare protein‐truncating deletion in SORL1 (rs1343336951; p.C1431fs). SORL1+/+ isogenic control iPSC lines were created from the patient lines using CRISPR/Cas9. After validation, the iPSC lines were differentiated into forebrain neurons and analyzed for endosomal trafficking defects. Additional analyses were completed in HEK293‐APPswe cells overexpressing SORL1 wild‐type (WT) or the C1431fs variant. Studies are underway that examine SORL1+/C1431fs microglia for defects in endolysosomal function.ResultSORL1+/C1431fs neurons have increased localization of APP in early endosomes (p = 0.002), endosomal swelling (p = 0.004), and greater numbers of early endosomes per cell (p = 0.018). We additionally observe SORL1+/C1431fs neurons trending toward increased secretion of Aβ42 compared to controls. In HEK293 cells, C1431fs increased secretion of Aβ42 (p < 0.01), Aβ40 (p < 0.01), as well as APP soluble α‐secretase (sAPPα; p < 0.01) and β‐secretase (sAPPβ; p < 0.01) cleavage products. We additionally found C1431fs led to increased secretion of soluble SORL1 (p < 0.01). Surface biotinylation revealed C1431fs led to lower levels of SORL1 detected at the cell surface (p < 0.05). Conversely, C1431fs increased the amount of surface APP (p < 0.05).ConclusionOur results indicate that a single gene copy of the SORL1 C1431fs variant is sufficient to induce neuronal defects in endosomal trafficking and APP processing. Our findings are consistent with previously reported results from similar studies of SORL1 in cultured neurons. Ongoing studies in SORL1+/C1431fs microglia and neurons will help broaden our understanding of the role SORL1 plays in regulating endolysosomal phenotypes in multiple cell types implicated in AD.
Cell type specific contributions of mTOR inhibition that drive neuroprotective mechanisms in Alzheimer’s disease
Authors: Haynes Kathryn A , Santos Diogo Francisco Silva , Williams Sean‐Paul Gerard , Hart Jason T , Lehman Alicia M , Eckels Seana E , Nepali Umesh , Reddy Aman , Finkel Toren , Rizzo Stacey J Sukoff 
Published: January 2025

AbstractBackgroundStudies investigating mTOR signaling provide compelling and reproducible evidence of the extension of lifespan across model organisms by treatment with the mTOR inhibitor rapamycin, and preclinical data suggests neuroprotective benefits of rapamycin in models of Alzheimer’s disease (AD). Rapamycin has potent immunosuppressive and autophagy activating effects though it remains unknown whether rapamycin’s neuroprotective and lifespan enhancing effects are achieved through modulating systemic inflammation, augmenting autophagy, or via some combination of modifying both these factors. Relatedly, the cellular and molecular mechanisms that contribute to rapamycin’s neuroprotective effects in AD remain unclear. The purpose of these studies is to identify the brain‐specific cell types that contribute to the protective effects of mTOR inhibition in progressive AD.MethodFor these studies we crossed a transgenic mouse model of familial early onset amyloid plaque deposition (5XFAD; JAX#034848) with a mouse genetically engineered with reduced mTOR expression to ∼25% of WT levels (mTORΔ/Δ). Previous studies have demonstrated that these mTOR hypomorph mice exhibit a 20% extension in lifespan. We then generated chimeric mice by crossing mTORΔ/Δ/5XFAD carriers to neuronal‐, microglial‐, and astrocyte‐specific Cre+ lines, resulting in mTOR expression reduced to 25% of WT except in the specific Cre+ cell type. Male and female subjects were evaluated longitudinally across the lifespan for measures of healthspan using a frailty assessment and compared to WT littermate controls.ResultOffspring from all crosses of mTORΔ/Δ; 5xFAD; and neuronal (Syn1‐cre; JAX#003966), astroglial (Gfap‐cre; JAX#012896) or microglial (Cx3cr1‐cre; JAX#025524) cre‐expressing mice were viable with cohorts bred to N = 10/sex/genotype/cre line for longitudinal lifespan and healthspan assessments. Evaluation of frailty scores assessed at 12 months of age reveal the expected increase in frailty in 5XFAD relative to WT littermate controls with reduced frailty scores in mTORΔ/Δ carrier mice including mTORΔ/Δ/5XFAD crosses.ConclusionThe present interim results confirm and extend the protective effects of ubiquitous reduction of mTOR expression. Ongoing studies in Cre+ lines will determine in which cell types reduced mTOR signaling is necessary for neuroprotection by comprehensive characterization of these models in functional assessments, AD biomarkers and relevant pathology.
Automated image segmentation uncovers the association of a microglial subtype defined by High CD74 Expression with cognitive decline
Authors: Taga Mariko , Fujita Masashi , Parghi Neelang , De Jager Philip L. 
Published: January 2025

AbstractBackgroundStage III activated microglia have been associated with Alzheimer’s Disease (AD) and cognitive decline. Separately, recent single‐cell RNA‐sequencing revealed CD74 as a marker gene that is enriched in immunologically active microglial subtypes associated with AD.MethodPost mortem tissue sections from the dorsolateral prefrontal cortex were stained simultaneously for (1) CD74, (2) IBA1 (a general microglial marker that outlines cellular processes), and (3) phosphoTau (AT8 antibody) to locate Tau proteinopathy. 154 aged individuals with and without AD from two brain collections were stained: ROS/MAP (n = 63) and NYBB (n = 91). To ensure unbiased results and facilitate high‐throughput data analysis, the entire tissue sections were scanned using a Nikon immunofluorescence scanner. An image analysis pipeline using CellProfiler software has been developed, to automatically delineate the grey and white matter and to extract microglial cell morphology and IBA1/CD74 intensities from a total of 483,733 neocortical microglia.ResultIn a meta‐analysis of the two datasets, the frequency of microglia with CD74 high expression (CD74high) is increased in individuals with a clinical diagnosis of AD dementia compared to those without (p = 0.01). These microglia exhibit significantly higher IBA1 intensity (p = 4.1 × 10‐20) and adopt a less complex, amoeboid shape (p = 1.1 × 10‐23) when compared to the remaining microglia. Results are consistent in samples from each of the contributing brain banks. Since we have a large surface area, we also analyzed the spatial distribution of CD74high cells and note heterogeneity in the distribution of these cells along the cortical ribbon, suggesting that their presence is influenced by regional factors. These topological analyses are ongoing, leveraging the tangle staining.ConclusionWe report a potential role of CD74high microglial cells in cognitive decline and present evidence that they have a morphologic characteristic that is shared with stage III microglia. Thus, we have used a new automated image segmentation pipeline optimized for the characterization of microglia to define and explore the functional characteristics and topological features of a microglial subtype associated with AD that was originally defined using single cell transcriptomic profiles.
NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) AI‐Enhanced Search
Authors: Greenfest‐Allen Emily , Valladares Otto , Gangadharan Prabhakaran , White Heather , Kuzma Amanda B , Kuksa Pavel P. , Lee Wan‐Ping , Leung Yuk Yee , Wang Li‐San 
Published: January 2025

AbstractBackgroundNIAGADS is a national data repository that offers qualified investigators access to genomic data for Alzheimer’s disease (AD) and related dementia. In addition, NIAGADS has made substantial effort to curate, harmonize, standardize, and disseminate AD‐relevant variant, gene, and sequence annotations from publications, functional genomics datasets, and summary statistics deposited at NIAGADS. These results are made available to the public in a collection of interactive knowledgebases (AD Variant Portal, FILER Functional Genomics Repository, VariXam, Alzheimer’s GenomicsDB & Genome Browser), all of which are accessible programmatically via the NIAGADS API. However, as these offerings grow, navigating them can be challenging. Here, we introduce AI‐based enhancements to NIAGADS sites to help guide researchers and facilitate data discovery.MethodWe leverage OpenAI’s generative AI to build and train three large language models (LLMs) based on NIAGADS documentation, step‐by‐step recipes for data‐access requests, subject‐specific vocabularies, and the OpenAPI specification defining the NIAGADS API that allows programmatic access to the NIAGADS knowledgebases. For users of the API and to enhance search interfaces, we build on the LLMs to construct a framework for handling complex natural language instructions that decomposes an inquiry into tasks and subtasks and then plans, selects, and optionally executes API calls and parses the results.ResultDeveloping these LLMs allows NIAGADS to improve user experiences by integrating topic‐specific chatbots and generative AI search tools into NIAGADS sites. Rule‐based chatbots that leverage conversational AI on the NIAGADS portal and Data Sharing Service will respond to inquiries with answers inferred from the LLMs, with responses improving with user feedback. These bots will also supplement help requests, suggesting solutions to common inquiries. Planner‐enhanced generative AI based on the API‐specification trained LLMs will be tied to knowledgebase searches and filters in resources such as the GenomicsDB and FILER to allow users to leverage natural language processing to ask sophisticated questions that require multiple API calls to resolve the answer.ConclusionIntroducing AI‐enhanced search creates an interactive opportunity for NIAGADS users to learn new information or discover resources and tools they can use to supplement their research, which, in turn, improves NIAGADS ability to support AD genetics research.
Expression of the APOE4 allele influences the systemic environment to alter hippocampal phenotypes
Authors: Philippi Sarah M , Ferreira Ana Catarina , Hemmer Brittany M. , BP Kailash , Kapoor Manav , Raj Towfique , Castellano Joseph M. 
Published: January 2025

AbstractBackgroundThe apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD), increasing risk from 3‐12‐fold relative to the common ε3 allele. Seminal studies have revealed that age‐related changes in blood‐CNS communication regulate cognitive function. More recently, youth‐associated blood‐borne proteins revitalize the aged brain, improving hippocampal function and increasing adult neurogenesis and dendritic spine plasticity. Characterizing plasma proteomic changes across various systemic contexts may thus be critical for development of novel therapeutic strategies to combat AD. We hypothesized that the plasma proteome differs between APOE4 and APOE3 individuals, and these systemic changes account for differences in brain function according to APOE genotype.MethodUsing an aptamer‐based platform to profile the plasma proteome from human APOE4/4 and APOE3/3 subjects, we identified allele‐specific changes in protein expression and canonical pathways linked to CNS functions and processes. Next, we examined the plasma proteome in APOE knock‐in mice expressing human APOE3 or APOE4 and evaluated those pathways that are conserved across species. To examine molecular processes within the brain regulated by opposing APOE alleles from the systemic environment, we characterized transcriptomic changes in the hippocampi of mice in which blood is shared between APOE4 and APOE3 mice by parabiosis relative to isogenic control pairs.ResultIn both mouse and human subjects, expression of APOE4 is associated with perturbations of plasma proteins related to extracellular matrix (ECM) and inflammation pathways relative to expression of APOE3. Several pathways shown to be associated with APOE3 expression in the hippocampus and disrupted in APOE4‐KI hippocampus were found to be restored in APOE4‐KI mice exposed to APOE3 blood via parabiosis. Specific deleterious phenotypes were identified in the hippocampi of APOE3 mice exposed to APOE4 blood, suggesting that APOE4‐associated brain phenotypes are, in part, mediated by how APOE4 alters the systemic compartment.ConclusionWe find that APOE alleles differentially alter the systemic environment to confer changes in brain phenotypes. Ongoing experiments focus on investigating the protective impact of the APOE3 systemic environment on molecular processes within the APOE4 hippocampus, which may ultimately inform our understanding of increased AD risk in APOE4 subjects.
Impact of APOE4 Allele on Cell‐Cell Communication and α‐Synuclein Aggregation in Lewy Body Dementia: Insights from Spatial Transcriptomics
Authors: Jin Yunjung , Wixom Alexander Q. , Li Zonghua , Liu Yuanhang , Koga Shunsuke , Sekiya Hiroaki , Santhakumar Hannah , Bu Guojun , Dickson Dennis W. , Zhao Na 
Published: January 2025

AbstractBackgroundThe aggregation of α‐synuclein protein, encoded by the SNCA gene, forms Lewy bodies (LBs) in neurons and is a key pathological feature of Lewy body dementia (LBD). Interestingly, the apolipoprotein E gene (APOE), primarily expressed in glial cells, is the strongest genetic modifier for LBD. The ε4 allele of this gene (APOE4) notably increases the risk of LBD. However, the specific mechanisms through which APOE‐regulated glial cells affect α‐synuclein aggregation in neurons are not yet fully understood.MethodTo explore this, we conducted spatial transcriptomics using the 10X Genomics Visium CytAssist platform on Formalin‐Fixed Paraffin‐Embedded tissue slides from the temporal cortex of human LBD brains (N = 4 brains in controls and N = 6 brains in LBD group, with an equal ratio of APOE3/3 and APOE3/4 genotypes). We defined the neuronal layers of the gray matter (Layers 1 to 6, L1‐6) and white matter in each brain based on the gene signature of each spot. We also identified LBs from hematoxylin and eosin (H&E) staining on the same slides, and annotated LB‐positive (LB+), LB‐surrounding and LB‐negative (LB‐) spots in each brain using Loupe Browser. We evaluated SNCA and APOE gene expression in each layer and analyzed cell‐cell communication using the CellChat tool across the layers.ResultWe observed that the SNCA gene was highly expressed in L5, which corresponded to the areas where most LBs were found. Notably, within LB+ spots across all layers, both SNCA and APOE gene expression levels were elevated in APOE3/4 cases compared to APOE3/3 cases. Furthermore, we identified cell‐cell communication networks between LB+ and LB‐surrounding spots, particularly in L4 and L5. These networks were enriched by microglia‐related signaling pathways, including APOE signaling, migration inhibitory factor (MIF) signaling, and colony stimulating factor 1 (CSF1) signaling. Interestingly, APOE3/4 brains exhibited significantly reduced interactions and lower interaction strength in these networks compared to APOE3/3 samples.ConclusionOur findings indicate that impaired cell‐cell communication, such as microglia‐mediated immune responses around LB regions, may be associated with the increased risk presented by the APOE4 allele in LBD brains.
NCRAD iPSCs: a vital resource for the Alzheimer’s disease research community
Authors: Nudelman Kelly N. , Jackson Trever , Marshall Jeanine D. , Faber Kelley M. , Ohlemacher Sarah K , Edler Michael C. , Foroud Tatiana M. , Meyer Jason S. 
Published: January 2025

AbstractBackgroundThe National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) is continuing to develop a bank of induced pluripotent stem cells (iPSCs) that are available by request to the Alzheimer’s disease (AD) research community.MethodsAs part of the pipeline for quality control of received cell lines, DNA was extracted for all lines and was submitted for whole genome sequencing (WGS). Paired‐end WGS data was generated using the Illumina NovaSeq 6000 and processed following GATK best practices using the Sentieon pipeline. WGS data was annotated with Annovar, and data was reviewed for reported cell line variants and checked with Varsome and Franklin. Sequencing data was reviewed for all nonsynonymous and splicing variants in the APP, PSEN1, PSEN2, GRN, and MAPT genes. Additionally, DNA from cell lines was genotyped in‐house by NCRAD to generate apolipoprotein E (APOE) genotypes, and this data was compared with the WGS to confirm sample identity. Basic clinical and demographic data was also collected, including sex, case/control status, age, race, and ethnicity.ResultsTo date, DNA has been extracted and genotyped at NCRAD for lines from 183 participants including generation of APOE genotypes passing quality control. Of these, 120 cell lines have returned WGS data passing quality control. Table 1 describes the demographic and clinical features for these lines, which include data for lines from 90 individuals as well as data for 30 isogenic lines. Of the 120 lines with available WGS, there are 13 case APP variant carriers, 13 case MAPT variant carriers, 8 case PSEN1 variant carriers, and 2 case PSEN2 variant carriers. Additionally, these cell lines included two control carriers of variants of uncertain significance (VUS) in GRN or PSEN2, as well as two cases carrying VUS in PSEN1 or APP.ConclusionsNCRAD continues to expand iPSCs for the research community; adding WGS data to this resource provides an expanded scope for pre‐screening as well as functional research. Future directions include review of variants being tested in the Model Organism Development & Evaluation for Late‐Onset AD (MODEL‐AD) to provide additional value to researchers.