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Zhao, Jing; Fu, Yuan; Yamazaki, Yu; Ren, Yingxue; Davis, Mary D; Liu, Chia-Chen; Lu, Wenyan; Wang, Xue; Chen, Kai; Cherukuri, Yesesri; Jia, Lin; Martens, Yuka A; Job, Lucy; Shue, Francis; Nguyen, Thanh Thanh; Younkin, Steven G; Graff-Radford, Neill R; Wszolek, Zbigniew K; Brafman, David A; Asmann, Yan W; Ertekin-Taner, Nilüfer; Kanekiyo, Takahisa; Bu, Guojun
Nature communications, 11/2020, Letnik: 11, Številka: 1Journal Article
APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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