@article{cc92376b56964a00a28289d21b697378,
title = "APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer{\textquoteright}s disease patient iPSC-derived cerebral organoids",
abstract = "APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer{\textquoteright}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.",
author = "Jing Zhao and Yuan Fu and Yu Yamazaki and Yingxue Ren and Davis, {Mary D.} and Liu, {Chia Chen} and Wenyan Lu and Xue Wang and Kai Chen and Yesesri Cherukuri and Lin Jia and Martens, {Yuka A.} and Lucy Job and Francis Shue and Nguyen, {Thanh Thanh} and Younkin, {Steven G.} and Graff-Radford, {Neill R.} and Wszolek, {Zbigniew K.} and Brafman, {David A.} and Asmann, {Yan W.} and Nil{\"u}fer Ertekin-Taner and Takahisa Kanekiyo and Guojun Bu",
note = "Funding Information: We are grateful to Dr. Yadong Huang and Chengzhong Wang for providing the APOE isogenic lines. This work was partially supported by Mayo Clinic Center for Regenerative Medicine, Neuroregeneration Lab. Lab Funding: This work was supported by NIH grants RF1AG051504, R37AG027924, RF1AG046205, RF1AG057181, R01AG066395, P01NS074969, and P30AG062677 (to G.B.), Younkin Fellowship and Alzheimer{\textquoteright}s Association Research Fellowship 2018-AARF-592302 (to J.Z.), and R01AG061796 (to N.E.-T.). Dr. Zbigniew K. Wszolek is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust, the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and by Albertson Parkinson{\textquoteright}s Research Foundation. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41467-020-19264-0",
language = "English (US)",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}