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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE239974 | 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:scRNAseq of Cd45+ cells from brains of ApoE-variant Alzheimer's mice sorted by ex-vivo amyloid beta uptake

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

Project description: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.

2023-12-29 | GSE239975 | 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.

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APOE-Ɛ4 astrocytes exhibit deficits in endocytic uptake that contribute to the delayed maturation of neuronal network activity and alter neuronal tau uptake in co-cultures of human iPSC-derived brain cells

Project description:To explore the mechanistic basis of ApoE Ɛ4 vs ApoE Ɛ3 protein expression on endocytic pathways responsible for tau uptake in neurons and astrocytes and the maturation of neuronal networks, we have developed genotype matched co-cultures of iPSC derived astrocytes and neurons derived from isogenic triads of iPSC lines generated by the ADAPTED consortium (Schmid et al., 2019, 2020) . We show that isogenic iPSC derived APOE-E4 expressing astrocytes take up less extracellular tau than APOE-E3 or APOE null astrocytes, while isogenic neurons in monoculture take up equivalent amounts of tau primarily through macropinocytosis. Co-culture of neurons with genotype matched astrocytes increases the general uptake capacity of neurons by increasing the dependence of neuronal endocytosis on dynamin mediated pathways. Co-culture also enhances the emergence of spontaneous neuronal activity; however, the emergence of synchronous network activity is impaired by the expression of APOE-E4 genotype. We performed RNA-Seq on the astrocytes, neurons and co-cultures to understand the molecular pathway changes associated with different ApoE genotypes.

2024-04-08 | GSE171700 | GEO

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

Project description:scRNAseq of Cd45+ cells from brains of Aducanumab-treated ApoE-variant Alzheimer's mice

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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

Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau

Project description:Alzheimer’s disease (AD) is an age-associated neurodegenerative disease characterized by amyloidosis, tauopathy, and activation of microglia, the brain resident innate immune cells. We show that a RiboTag translational profiling approach can bypass biases due to cellular enrichment/cell sorting. In our recent study entitled “Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau”, we utilized data acquired using this approach in models of amyloidosis, tauopathy, and aging, to reveal a common set of alterations and identified a central APOE-driven network that converged on CCL3 and CCL4 across all conditions. Notably, examination of the aged female dataset demonstrated a significant exacerbation of many of these shared transcripts in this APOE network, revealing a potential mechanism for increased AD susceptibility in females. This study has broad implications for microglial transcriptomic approaches and provides new insights into microglial pathways associated with different pathological aspects of aging and AD.

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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge [Spatial transcriptomics]

Project description:The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response – two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1a expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.

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Multi-omic comparison of Alzheimers variants in human ESC-derived microglia reveals convergence at APOE

Project description:Variations in many genes linked to sporadic Alzheimers 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 A-beta uptake in an APOE-dependent manner in vitro, and attenuated A-beta 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

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CD45 deficiency drives amyloid-? peptide oligomers and neuronal loss in Alzheimer's disease mice.

Project description:Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-? peptide (A?) but deficient in CD45 (PSAPP/CD45(-/-) mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble A?, decreased plasma soluble A?, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-? and interleukin-1?, and neuronal loss in PSAPP/CD45(-/-) mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-A? phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated A? oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45(-/-) mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic A? oligomers and validate CD45-mediated microglial clearance of oligomeric A? as a novel AD therapeutic target.

| S-EPMC3068193 | biostudies-literature

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