APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids

Jing Zhao, Yuan Fu, Yu Yamazaki, Yingxue Ren, Mary D. Davis, Chia-Chen Liu, Wenyan Lu, Xue Wang, Kai Chen, Yesesri Cherukuri, Lin Jia, Yuka A. Martens, Lucy Job, Francis Shue, Thanh Thanh Nguyen, Steven G. Younkin, Neill R. Graff-Radford, Zbigniew K. Wszolek, David A. Brafman, Yan W. Asmann, Nilüfer Ertekin-Taner, Takahisa Kanekiyo and Guojun Bu ()
Additional contact information
Jing Zhao: Mayo Clinic
Yuan Fu: Mayo Clinic
Yu Yamazaki: Mayo Clinic
Yingxue Ren: Mayo Clinic
Mary D. Davis: Mayo Clinic
Chia-Chen Liu: Mayo Clinic
Wenyan Lu: Mayo Clinic
Xue Wang: Mayo Clinic
Kai Chen: Mayo Clinic
Yesesri Cherukuri: Mayo Clinic
Lin Jia: Mayo Clinic
Yuka A. Martens: Mayo Clinic
Lucy Job: Mayo Clinic
Francis Shue: Mayo Clinic
Thanh Thanh Nguyen: Mayo Clinic
Steven G. Younkin: Mayo Clinic
Neill R. Graff-Radford: Mayo Clinic
Zbigniew K. Wszolek: Mayo Clinic
David A. Brafman: Arizona State University
Yan W. Asmann: Mayo Clinic
Nilüfer Ertekin-Taner: Mayo Clinic
Takahisa Kanekiyo: Mayo Clinic
Guojun Bu: Mayo Clinic

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19264-0

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