APOE4-dependent transcriptome changes in human iPSC-derived astrocytes
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PROVIDER: PRJNA850014 | ENA |
REPOSITORIES: ENA
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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
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
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
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 | GSE215444 | GEO
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
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 | GSE215446 | GEO
Project description:The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Ab42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Ab uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Ab phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant.
2018-05-31 | GSE102956 | GEO
Project description:Here we elucidate the effect of Alzheimer’s disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9 and APPswe, on functionality of human microglia. We present a physiologically relevant high-yield protocol for producing human microglia-like cells (iMGLs) from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to recreate microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.
2019-10-08 | GSE135707 | GEO
Project description:We generated a stable healthy and diseased (with ALS-linked FUS-R521H mutation) iPSC line containing the coding sequence of SOX9 under a Tet-on promotor in the safe harbor AAVS1 locus via recombinase-mediated cassette exchange. This allows the induction of SOX9 expression after doxycycline addition and generates in this way PSC-derived astrocytes. RNASeq is performed on these healthy and diseased iSOX9-astrocytes at an early and late timepoint. In addition, we included commercially available PSC-derived astrocytes (called "iCell") and fetal human primary astrocytes (called "fHA").
2021-05-10 | GSE162892 | GEO
Project description:RNA sequencing on iPSC-derived iSOX9-astrocytes
| PRJNA683648 | ENA