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APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE215447 | GEO | 2022/10/20

REPOSITORIES: GEO

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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

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

| PRJNA890284 | ENA

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

Transcriptional heterogeneity and lineage commitment in myeloid progenitors

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-11-25 | E-GEOD-72859 | biostudies-arrayexpress

PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma

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

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Altered mitochondrial dynamics and function in APOE4-expressing astrocytes.

Project description:APOE4 is a major risk factor for sporadic Alzheimer's disease; however, it is unclear how it exerts its pathological effects. Others and we have previously shown that autophagy is impaired in APOE4 compared to APOE3 astrocytes, and demonstrated differences in the expression of mitochondrial dynamics proteins in brains of APOE3 and APOE4 transgenic mice. Here, we investigated the effect of APOE4 expression on several aspects of mitochondrial function and network dynamics, including fusion, fission, and mitophagy, specifically in astrocytes. We found that APOE3 and APOE4 astrocytes differ in their mitochondrial dynamics, suggesting that the mitochondria of APOE4 astrocytes exhibit reduced fission and mitophagy. APOE4 astrocytes also show impaired mitochondrial function. Importantly, the autophagy inducer rapamycin enhanced mitophagy and improved mitochondrial functioning in APOE4 astrocytes. Collectively, the results demonstrate that APOE4 expression is associated with altered mitochondrial dynamics, which might lead to impaired mitochondrial function in astrocytes. This, in turn, may contribute to the pathological effects of APOE4 in Alzheimer's disease.

| S-EPMC7382473 | biostudies-literature

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