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ScRNAseq of Cd45+ cells from brains of Aducanumab-treated ApoE-variant Alzheimer's mice

ABSTRACT: Here we perform single cell sequencing to examine the impact of aducanumab treatment on the transcriptome of immune cells of aged AD mice bearing knock-in of human APOE variants in the murine APOE locus, treated either with aducanumab or an IgG control.

ORGANISM(S): Mus musculus

PROVIDER: GSE239975 | GEO | 2023/12/29

REPOSITORIES: GEO

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scRNAseq of Cd45+ cells from brains of ApoE-variant Alzheimer's mice sorted by ex-vivo amyloid beta uptake

Project description:Here we perform single cell sequencing of immune cells of aged AD mice bearing knock-in of human APOE variants in the murine APOE locus, sorted into high-uptake and low-uptake pools after incubation with fluorescently labeled amyloid beta.

2023-12-29 | GSE239974 | GEO

Bulk RNA sequencing of Cd45+ cells from brains of aged Alzheimer's mice bearing human APOE knockin

Project description:Here we perform bulk RNA sequencing of immune cells of aged AD mice bearing knock-in of human APOE variants in the murine APOE locus.

2023-12-29 | GSE239977 | GEO

scRNAseq and scATACseq of Cd45+ cells from brains of 5XFAD mice bearing distinct APOE alleles and across age

Project description:Here we analyze the gene expression and chromatin accessibility landscape of immune cells in the brains of 5XFAD mice, a common model of Alzheimer's disease, bearing knock-in of human APOE variants in the mouse APOE locus, and aged to 10, 20, 60, or 96 weeks of age.

2023-12-29 | GSE225503 | GEO

mRNA sequencing of brain and liver in multiple Alzheimer's Disease mouse models after treatment with either a Non-Targeting Control siRNA or an siRNA targeting mouse Apoe mRNA

Project description:The most common genetic risk factor for late onset Alzheimer Disease (AD) is the APOE4 allele, with evidence for gain- and loss-of-function as a primary mechanism. ApoE knockout in mice abrogates AD phenotypes but causes severe atherosclerosis due to the role of liver ApoE in cholesterol homeostasis. Previous attempts to therapeutically block brain-specific ApoE in adult models of AD only modestly reduced ApoE expression and no significant impact on amyloid burden. Here, we optimized a divalent siRNA (di-siRNA) to selectively silence ApoE in brain (>2 months). By measuring transcriptomic changes upon knockdown of ApoE in the CNS in multiple mouse models of AD, we find that ApoE knockdown results in an upregulation of the innate immune response, likely through activation of microglia. Additionally, we find that the changes in the transcriptome were similar, but not identical, two weeks and two months post-treatment. We find that mild reduction of ApoE in the liver does not cause widespread transcriptomic changes, but near complete knockdown of ApoE in the liver results in the dysregulation of many lipid metabolism-related pathways.

2023-10-02 | GSE186756 | GEO

Small RNA sequencing of brain-derived extracellular vesicles from post-mortem brain tissue of controls and Alzheimer's disease patients with different APOE genotypes

Project description:Using a recently optimized method for separation of brain-derived EVs (bdEVs) from post-mortem tissues, we obtained bdEVs of 23 AD patients with different APOE genotypes and 7 controls. RNA was extracted from brain homogenate, an intermediate ("10K") EV fraction, and more purified EVs and subjected to small RNA sequencing. Numerous RNA species varied with AD pathology and APOE genotypes. Dysregulation of some of these molecules has been implicated in amyloid processing, neurodegeneration and metabolic functions. Molecular differences of bdEVs may thus reflect or play a role in modulating AD progression.

2020-10-20 | GSE159541 | GEO

APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia

Project description:The major genetic risk factor for Alzheimer’s disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.

2024-10-04 | GSE252454 | GEO

Peripheral immunomodulatory effects of Apolipoprotein E4 on Alzheimer's disease - Immune Enrichment

Project description:Apolipoprotein E (APOE) is a lipid and cholesterol transport molecule known to influence Alzheimer's disease (AD) risk in an isoform-specific manner. In particular, the APOE E4 allele is the largest genetic risk factor for late-onset sporadic AD. Our recent findings uncovered activated, clonally expanded T cells in AD cerebrospinal fluid (CSF). This T cell phenotype occurred concomitantly with altered expression of APOE in CSF monocytes. Yet, whether APOE variants differentially affect peripheral immunity systems remains unknown. In this study, we performed targeted immune profiling using single-cell epigenetic and transcriptomic analysis of peripheral blood mononuclear cells (PBMC). We analyzed 55 age-matched healthy control (HC) and AD patients with equal distribution of APOE E3/E3, E3/E4, and E4/E4 genotypes. We reveal dysregulation in monocytes and clonally expanded T cells that are distinct to AD patients carrying the APOE E4/E4 genotype. Additionally, we find APOE isoform-dependent chromatin accessibility differences that correspond to RNA expression changes. Cumulatively, these results uncover APOE isoform-dependent changes to peripheral immunity in AD.

2024-03-22 | GSE227991 | GEO

Expression data from post mortem Alzheimer's disease brains

Project description:To identify molecular pathological alterations in AD brains, we performed interspecies comparative microarray analyses using RNAs prepared from postmortem human brain tissues donated for the Hisayama study and hippocampal RNAs from the triple-transgenic mouse model of AD (3xTg-AD) Three-way ANOVA of microarray data from frontal cortex, temporal cortex and hippocampus with presence/absence of AD and vascular dementia, and sex, as factors revealed that the gene expression profile is most significantly altered in the hippocampi of AD brains. Comparative analyses of the brains of AD patients and a mouse model of AD showed that genes involved in non-insulin dependent DM and obesity were significantly altered in both, as were genes related to psychiatric disorders and Alzheimer’s disease. We prepared RNA samples from the gray matter of frontal and temporal cortices and hippocampi derived from 88 postmortem brains, among which 26 cases were pathologically diagnosed as having AD or an AD-like disorder. High-quality RNA (RIN≧6.9) samples were subjected to microarray analysis using the Affymetrix Human Gene 1.0 ST platform, and only those results that passed examinations for quality assurance and quality control of the Human Gene 1.0 ST arrays were retrieved. In total, we obtained gene expression profiles from the following samples: 33 frontal cortex samples, among which 15 were from AD patients; 29 temporal cortex samples, among which 10 were from AD patients; 17 hippocampus samples, among which seven were from AD patients

2013-04-17 | E-GEOD-36980 | biostudies-arrayexpress

Neuronal ApoE Upregulates MHC-I Expression to Drive Selective Neurodegeneration in Alzheimer’s Disease

Project description:Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish while others remain resilient are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that apoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of apoE—which has a robust genetic linkage to AD—correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wildtype mice, human apoE knock-in mice, and humans with or without AD. Elimination or over-expression of neuronal apoE revealed a causal relationship between apoE expression, neuronal MHC-I expression, Tau pathology, and neurodegeneration. Functional reduction of MHC-I ameliorated Tau pathology in apoE4-expressing primary neurons and in mouse hippocampi expressing pathological Tau. These findings suggest a mechanism linking neuronal apoE expression to MHC-I expression and, subsequently, to Tau pathology and selective neurodegeneration.

2021-04-19 | GSE167497 | GEO

Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [ATAC-seq]

Project description:Variations in many genes linked to sporadic Alzheimer’s disease (AD), show abundant expression in microglia, however, relationships between these genes remain largely elusive. Here, we establish isogenic human ES-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1 and TREM2 loci, and curate a comprehensive atlas comprising ATACseq, ChIPseq, RNAseq and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates upregulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, where SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL Aβ uptake in an APOE-dependent manner in vitro, and attenuated Aβ uptake/clearance in mouse AD brain xenotransplants. Utilizing this modeling and analysis platform for human microglia, we provide new insight into epistatic interactions in AD genes and demonstrate convergence of microglial AD genes at the APOE locus.

2020-09-01 | GSE153654 | GEO

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