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APOE4-dependent transcriptome changes in human iPSC-derived astrocytes

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206314 | GEO | 2023/08/31

REPOSITORIES: GEO

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Project description:APOE4 is the major genetic risk factor for sporadic Alzheimers disease (AD). Although APOE4 is well known to promote Abeta pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n=5 APOE3 and n=5 APOE4), using a combination of anti-pTau PHF1 (pS396/pS404) immunoprecipitation and mass spectrometry. This proteomic approach was complemented by a neuropathological analysis of anti-pTau PHF1 and anti-Abeta 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n=11 APOE3 and n=10 APOE4). Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOE3 and APOE4 groups (FC over 1.50, IPPHF1 versus IPIgG ctrl). We identified 80 and 68 proteins as strong pTau interactors in APOE3 and APOE4 groups, respectively (SAINT score above 0.80; FDR under 5%). A total of 47/80 proteins were identified as strong pTau interactors only for APOE3 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as strong pTau interactors only for APOE4 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A comprehensive characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE4 cases. Our study supports an influence of APOE genotype on pTau subcellular location in the human brain. These results are consistent with a facilitation of pTau progression to Abeta-affected brain regions of APOE4 carriers, paving the way to the identification of potential new therapeutic targets. This entry contains the mass spectrometric raw files for the immune purifications.

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APOE4-dependent transcriptome changes in human iPSC-derived astrocytes

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