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Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [isogenicAPOE]

ABSTRACT: Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [isogenicAPOE]

PROVIDER: PRJNA786225 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17130900_1.fastq.gz	Fastqsanger.gz
	SRR17130900_2.fastq.gz	Fastqsanger.gz
	SRR17130901_1.fastq.gz	Fastqsanger.gz
	SRR17130901_2.fastq.gz	Fastqsanger.gz
	SRR17130902_1.fastq.gz	Fastqsanger.gz

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Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes

Project description:Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes

| PRJNA786227 | ENA

Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [populationAPOE]

Project description:The impact of Apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cell models, post-mortem brain and APOE targeted replacement mice. Population and isogenic models uncover that APOE4 local haplotype rather than a single risk allele alone contributes to the risk. Global transcriptomic analyses reveal human specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 leads to elevated de novo cholesterol synthesis despite the intracellular cholesterol accumulation due to lysosomal sequestration of cholesterol in astrocytes. Transcriptome analyses uncovered Matrisome dysregulation associated with upregulated chemotaxis, glial activation and lipid biosynthesis in astrocytes, co-cultured with neurons that recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

2022-06-23 | GSE190187 | GEO

Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [mouseApoe]

2022-06-23 | GSE190186 | GEO

Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [isogenicAPOE]

2022-06-23 | GSE190185 | GEO

Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [mouseApoe]

Project description:Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [mouseApoe]

| PRJNA786226 | ENA

Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [populationAPOE]

Project description:Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes [populationAPOE]

| PRJNA786229 | ENA

ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes

Project description:Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer’s disease (AD). Among them, genetic variant e4 of the APOE gene (ApoE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human-induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagic flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.

2023-09-12 | PXD045298 | Pride

Cholesterol and matrisome pathways dysregulated in astrocytes and microglia.

Project description:The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

| S-EPMC9340815 | biostudies-literature

Cholesterol and matrisome pathways dysregulated in APOE ε4 human microglia and astrocytes

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-23 | GSE190188 | 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

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