REPORTALZHEIMER’S DISEASE

APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia

1. View ORCID ProfileGrzegorz Sienski1,*,†, 
2. View ORCID ProfilePriyanka Narayan1,2,3,*, 
3. View ORCID ProfileJulia Maeve Bonner1,2,*, 
4. View ORCID ProfileNora Kory1, 
5. View ORCID ProfileSebastian Boland4, 
6. Aleksandra A. Arczewska5,†, 
7. View ORCID ProfileWilliam T. Ralvenius2, 
8. View ORCID ProfileLeyla Akay2, 
9. View ORCID ProfileElana Lockshin2, 
10. Liang He6, 
11. Blerta Milo2, 
12. View ORCID ProfileAgnese Graziosi2, 
13. View ORCID ProfileValeriya Baru1,‡, 
14. View ORCID ProfileCaroline A. Lewis1, 
15. View ORCID ProfileManolis Kellis7,8, 
16. View ORCID ProfileDavid M. Sabatini1,7,9,10,11, 
17. View ORCID ProfileLi-Huei Tsai2,7,§ and 
18. Susan Lindquist1,9,10,||




Abstract 

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.

doi: 10.1126/scitranslmed.aaz4564.

• PMID: 33658354