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

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

PROVIDER: PRJNA786229 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17132600_1.fastq.gz	Fastqsanger.gz
	SRR17132600_2.fastq.gz	Fastqsanger.gz
	SRR17132602_1.fastq.gz	Fastqsanger.gz
	SRR17132602_2.fastq.gz	Fastqsanger.gz
	SRR17132604_1.fastq.gz	Fastqsanger.gz

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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

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 [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 [isogenicAPOE]

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

| PRJNA786225 | 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 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

Effect of dietary cholesterol on gene expression in the liver of apoE-KO mice

Project description:Apolipoprotein E-knock out (apoE-KO) mouse is known as a model animal for atherosclerosis accompanied by spontaneous hypercholesterolemia. When apoE-KO mice were fed a chow supplemented with 1.25% cholesterol (high-Chol diet), cholesterol and bile acids were highly increased in the liver within a week. However, the amount of triacylglycerol (TG) in very low-density lipoprotein (VLDL), but not in the liver, was reduced by 78%. The epididymal adipose tissue was almost diminished in the long term. Cholesterol metabolism is tightly regulated by both cholesterol and its metabolites in the mammalian liver, but the regulatory mechanism of TG synthesis remains to be elucidated. To evaluate the impact of high-Chol diet for 1 week on gene expression in the liver of apoE-KO mice, DNA microarray analysis was performed with comparison to apoE-KO mice fed a normal chow. We found that mRNA expression related to lipid metabolism was suppressed by the high-Chol diet in the liver of apoE-KO mice, which includes beta-oxidation and glycerol-3-phosphate (G3P) pathway for TG synthesis. In particular, the mRNA and protein expression of lipin-1 and lipin-2 was markedly decreased. PGC-1?, which up-regulates the transcription of lipin-1, was also suppressed. Lipin is reported to function as a coactivator of PGC-1? and is an inducible amplifier of PPAR?, indicating that the suppression of genes involved in beta-oxidation could be induced by suppression of the lipins. These data using apoE-KO mice indicate that cholesterol and its metabolites are involved in regulating TG metabolism through a suppression of lipin-1 and lipin-2 in the liver. This research provides evidence for the mechanism of lipin expression in the liver. Apo E-KO mice at 10 weeks of age were fed normal chow (control) or high-Chol diet containing 1.25% cholesterol for 1 week. Three independent experiments were performed at each diet.

2011-08-07 | E-GEOD-27457 | biostudies-arrayexpress

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