APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia.

1. Sci Transl Med. 2021 Mar 3;13(583):eaaz4564. doi: 10.1126/scitranslmed.aaz4564.

APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia.

Sienski G(1), Narayan P(1)(2)(3), Bonner JM(1)(2), Kory N(1), Boland S(4), Arczewska AA(5), Ralvenius WT(2), Akay L(2), Lockshin E(2), He L(6), Milo B(2), Graziosi A(2), Baru V(1), Lewis CA(1), Kellis M(7)(8), Sabatini DM(1)(7)(9)(10)(11), Tsai LH(12)(7), Lindquist S(1)(9)(10).

Author information: (1)Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. (2)Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA. (3)Genetics and Biochemistry Branch, NIDDK, National Institutes of Health, Bethesda, MD 20814, USA. (4)Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. (5)Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. (6)Duke University, Durham, NC 27708, USA. (7)Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. (8)Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (9)Massachusetts Institute of Technology, Cambridge, MA 02142, USA. (10)Howard Hughes Medical Institute, Cambridge, MA 02139, USA. (11)Koch Institute for Integrative Cancer Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, MA 02139, USA. (12)Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA. lhtsai@mit.edu.

Erratum in Sci Transl Med. 2026 Jan 21;18(833):eaee9871. doi: 10.1126/scitranslmed.aee9871.

The E4 allele of the apolipoprotein E gene (APOE) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer’s disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several neurodegenerative diseases including AD. However, it is unclear how APOE4 perturbs the intracellular lipid state. Here, we report that APOE4, but not APOE3, disrupted the cellular lipidomes of human induced pluripotent stem cell (iPSC)-derived astrocytes generated from fibroblasts of APOE4 or APOE3 carriers, and of yeast expressing human APOE isoforms. We combined lipidomics and unbiased genome-wide screens in yeast with functional and genetic characterization to demonstrate that human APOE4 induced altered lipid homeostasis. These changes resulted in increased unsaturation of fatty acids and accumulation of intracellular lipid droplets both in yeast and in APOE4-expressing human iPSC-derived astrocytes. We then identified genetic and chemical modulators of this lipid disruption. We showed that supplementation of the culture medium with choline (a soluble phospholipid precursor) restored the cellular lipidome to its basal state in APOE4-expressing human iPSC-derived astrocytes and in yeast expressing human APOE4 Our study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the APOE4 genotype. Our study suggests that manipulating lipid metabolism could be a therapeutic approach to help alleviate the consequences of carrying the APOE4 allele.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

DOI: 10.1126/scitranslmed.aaz4564 PMCID: PMC8218593 PMID: 33658354 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: SL was a co-founder of Yumanity Therapeutics. LHT is a member of the Scientific Advisory Board of Yumanity Therapeutics. PN and SL are co-inventors on US Patent PCT/US2015/049674 (Cells expressing Apolipoprotein E and uses thereof). GS, PN, JMB, LHT are co-inventors on patent application 63/023,698 (Use of choline supplementation as therapy for APOE4-related disorders). GS and AAA are currently employees and shareholders of AstraZeneca. CAL is a paid consultant for ReviveMed Inc.