Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-19264-0
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Funding
- NIH [RF1AG051504, R37AG027924, RF1AG046205, RF1AG057181, R01AG066395, P01NS074969, P30AG062677]
- Younkin Fellowship
- Alzheimer's Association Research Fellowship [2018-AARF-592302, R01AG061796]
- Mayo Clinic Center for Regenerative Medicine
- Haworth Family Professorship in Neurodegenerative Diseases fund
- Albertson Parkinson's Research Foundation
- Donald G. and Jodi P. Heeringa Family
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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 epsilon 3/epsilon 3 or epsilon 4/epsilon 4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE epsilon 4/epsilon 4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of A beta 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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