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APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes

ABSTRACT: APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes

PROVIDER: PRJNA890284 | ENA |

REPOSITORIES: ENA

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APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (Spatial)

Project description:Apolipoprotein 4 (APOE4), is the strongest genetic risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor of Apoe while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional neuro-immunometabolism, however insights into the molecular constituents driving these responses remain unclear. Utilizing complimentary approaches across humanized ApoE expressing mice and isogenic IPS astrocytes, we demonstrate that harboring ApoE4 alters astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings demonstrate that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at the single-cell and spatially-resolved domains, which driven, in-part, by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation abrogated inflammatory-induced glycolytic shift and ultimately resulted in significantly dampened glycolysis-associated metabolites in tandem with mitigating production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.

2022-10-20 | GSE215445 | GEO

APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (scRNA-Seq)

2022-10-20 | GSE215444 | GEO

APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (bulk RNA-Seq)

2022-10-20 | GSE215446 | GEO

APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (Spatial)

Project description:APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (Spatial)

| PRJNA890289 | ENA

APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (scRNA-Seq)

Project description:APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (scRNA-Seq)

| PRJNA890285 | ENA

APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (bulk RNA-Seq)

Project description:APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (bulk RNA-Seq)

| PRJNA890288 | ENA

APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes

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

2022-10-20 | GSE215447 | GEO

APOE4-dependent transcriptome changes in human iPSC-derived astrocytes

Project description:APOE4 genotype is the strongest risk factor for the pathogenesis of sporadic Alzheimer’s disease (AD), but the detailed molecular mechanism of APOE4-mediated synaptic impairment remains to be determined in human cellular context. In this study, we generated human astrocyte model carrying APOE3 or APOE4 genotype using human induced pluripotent stem cells (iPSCs), in which isogenic APOE4 iPSCs were genome-edited from healthy control APOE3 iPSCs. By transcriptome analysis of human astrocytes between APOE genotypes, we showed the upregulation of an extracellular matrix glycoprotein in human APOE4 astrocytes, which may cause synaptic degeneration in concert with the equivocal reactive character and lipid change. Together, these results demonstrate novel negative impact of human APOE4 astrocyte on synaptic integrity and lead to a promising therapeutic intervention into APOE4-carriers.

2023-08-31 | GSE206314 | GEO

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

Comparaison of APOE4 and APOE3 transcriptomic profiles from derived cell lines in absence or presence of an inflammatory stimulus

Project description:Our objective was to study some of the molecular changes that associate with APOE4, ultimately aiming at identifying new mechanisms that support exacerbated neuroinflammation as a cause of functional deterioration in Alzheimer's disease (AD). We hypothesize that the increased risk of developing AD in APOE4 carriers could be the consequence of altered inflammatory regulatory functions in astrocytes, which would be key effectors of the pathological process.

2021-02-01 | E-MTAB-9625 | biostudies-arrayexpress

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