RRC ID 77519
Author Watanabe H, Murakami R, Tsumagari K, Morimoto S, Hashimoto T, Imaizumi K, Sonn I, Yamada K, Saito Y, Murayama S, Iwatsubo T, Okano H.
Title Astrocytic APOE4 genotype-mediated negative impacts on synaptic architecture in human pluripotent stem cell model.
Journal Stem Cell Reports
Abstract The 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 this study, we generated a human astrocyte model carrying the APOE3 or APOE4 genotype using human induced pluripotent stem cells (iPSCs) in which isogenic APOE4 iPSCs were genome edited from healthy control APOE3 iPSCs. Next, we demonstrated that the astrocytic APOE4 genotype negatively affects dendritic spine dynamics in a co-culture system with primary neurons. Transcriptome analysis revealed an increase of EDIL3, an extracellular matrix glycoprotein, in human APOE4 astrocytes, which could underlie dendritic spine reduction in neuronal cultures. Accordingly, postmortem AD brains carrying the APOE4 allele have elevated levels of EDIL3 protein deposits within amyloid plaques. Together, these results demonstrate the novel deleterious effect of human APOE4 astrocytes on synaptic architecture and may help to elucidate the mechanism of APOE4-linked AD pathogenesis.
Volume 18(9)
Pages 1854-1869
Published 2023-9-12
DOI 10.1016/j.stemcr.2023.08.002
PII S2213-6711(23)00301-6
PMID 37657448
PMC PMC10545487
MeSH Apolipoprotein E3 / genetics Apolipoprotein E4 / genetics Astrocytes Calcium-Binding Proteins Cell Adhesion Molecules Genotype Humans Induced Pluripotent Stem Cells* Pluripotent Stem Cells*
IF 6.032
DNA material pENTR4-H1 (RDB04395) CS-RfA-CG (RDB04390) pCMV-VSV-G (RDB04392) pCAG-HIVgp (RDB04394)