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

• Published in: Nature communications Vol. 11; no. 1; pp. 5540 - 14
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.11.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/106; 631/378/1689/1283; 631/80/304; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Apolipoprotein E; Apolipoprotein E3 - genetics; Apolipoprotein E3 - metabolism; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apoptosis; Cognition; Conversion; Dementia disorders; Gene Expression Regulation; Gene sequencing; Genotype; Genotypes; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - metabolism; Inhibitory postsynaptic potentials; multidisciplinary; Neurodegeneration; Neurodegenerative diseases; Organoids; Organoids - metabolism; Organoids - pathology; Pathogenesis; Patients; Phenotypes; Pluripotency; Ribonucleic acid; Risk analysis; Risk factors; RNA; RNA - metabolism; Science; Science (multidisciplinary); Stem cells; Synapses; Synapses - metabolism; Tau protein; Transcriptome; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19264-0

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. APOE4 is a strong genetic risk factor for late-onset Alzheimer’s disease. Here, the authors show that APOE4 is associated with AD features in hiPSCs-derived cerebral organoids. Isogenic conversion of APOE4 to APOE3 attenuates the AD-associated phenotype.