{"id":"doi:10.1038/s41467-020-19264-0","kind":"article","title":"APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids","authors":["Zhao J","Fu Y","Yamazaki Y","Ren Y","Davis MD","Liu CC","Lu W","Wang X","Chen K","Cherukuri Y","Jia L","Martens YA","Job L","Shue F","Nguyen TT","Younkin SG","Graff-Radford NR","Wszolek ZK","Brafman DA","Asmann YW","Ertekin-Taner N","Kanekiyo T","Bu G"],"author_count":23,"year":2020,"published":"2020-11-02","venue":"Nature communications","cited_by":329,"doi":"10.1038/s41467-020-19264-0","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-020-19264-0","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-020-19264-0","updated":null,"pmid":"33139712","pmcid":"PMC7608683","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC7608683/pdf","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.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids\" by Zhao J, Fu Y, Yamazaki Y et al., https://doi.org/10.1038/s41467-020-19264-0, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"organoids","name":"Organoids & Organ-on-Chip","domain_slug":"biotech"}],"cited_in_dossiers":[]}