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- Title
Apolipoprotein E regulates lipid metabolism and α-synuclein pathology in human iPSC-derived cerebral organoids.
- Authors
Zhao, Jing; Lu, Wenyan; Ren, Yingxue; Fu, Yuan; Martens, Yuka A.; Shue, Francis; Davis, Mary D.; Wang, Xue; Chen, Kai; Li, Fuyao; Liu, Chia-Chen; Graff-Radford, Neill R.; Wszolek, Zbigniew K.; Younkin, Steven G.; Brafman, David A.; Ertekin-Taner, Nilüfer; Asmann, Yan W.; Dickson, Dennis W.; Xu, Ziying; Pan, Meixia
- Abstract
APOE4 is a strong genetic risk factor for Alzheimer's disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.
- Subjects
DISEASE risk factors; APOLIPOPROTEIN E; APOLIPOPROTEIN E4; LEWY body dementia; ORGANOIDS; LIPID metabolism; ALZHEIMER'S disease
- Publication
Acta Neuropathologica, 2021, Vol 142, Issue 5, p807
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-021-02361-9