Apolipoprotein E regulates lipid metabolism and α-synuclein pathology in human iPSC-derived cerebral organoids

Jing Zhao, Wenyan Lu, Yingxue Ren, Yuan Fu, Yuka A. Martens, Francis Shue, Mary D. Davis, Xue Wang, Kai Chen, Fuyao Li, Chia Chen Liu, Neill R. Graff-Radford, Zbigniew K. Wszolek, Steven G. Younkin, David A. Brafman, Nilüfer Ertekin-Taner, Yan W. Asmann, Dennis W. Dickson, Ziying Xu, Meixia PanXianlin Han, Takahisa Kanekiyo, Guojun Bu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)807-825
Number of pages19
JournalActa Neuropathologica
Volume142
Issue number5
DOIs
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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