APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation
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1-s2.0-S2213671121003830-main.pdf
Description
Published version
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2.83 MB
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Unknown
Checksum (MD5)
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Author(s)
Lee, Se-In
Jeong, Woojin
Lim, Heejin
Cho, Sukhee
Lee, Hyein
Jang, Yonghee
Cho, Joonho
Bae, Simsung
Lin, Yuan-Ta
Tsai, Li-Huei
Date Issued
September 2021
Journal
Stem Cell Reports
Publisher
Elsevier BV
Citation
Lee, Se-In, Jeong, Woojin, Lim, Heejin, Cho, Sukhee, Lee, Hyein et al. 2021. "APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation." Stem Cell Reports, 16 (9).
Version
Final published version
Abstract
The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer's disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aβ production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aβ secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aβ production through an oversupply of cholesterol.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.stemcr.2021.07.017
