APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation
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Abstract Background: The onset of Alzheimer’s disease (AD) typically occurs later in life. Recent genetic analysis of patients and unaffected individuals revealed multiple genetic variants associated with late-onset AD. One of the strongest genetic risk factors for AD is 𝜀4 allele of APOE encoding apolipoprotein (ApoE), which is predominantly expressed in astrocytes. The role and mechanism of ApoE in initiating AD-associated pathologies, including amyloid-β (Aβ) accumulation and neurodegeneration in neurons, remains to be elucidated.Methods: Human induced pluripotent stem cells (hiPSCs) from healthy individuals and isogenic cells in which the ApoE 𝜀3 allele was replaced with an 𝜀4 allele were selected to generate human neurons and astrocytes. To investigate the effect of astrocytic ApoE4 on neuronal Aβ production, iPSC-derived neurons carrying the ApoE 𝜀3 allele were cultured in conditioned media from healthy iPSC-derived astrocytes (ApoE3/E4 heterozygote) for five weeks. Then, the media were replaced with either ApoE3 or ApoE4 astrocyte conditioned media (ACM), cultured for four days, and neuronal amyloid precursor protein (APP) expression and Aβ production were measured. To determine potential mechanisms for upregulation of APP in neurons by ApoE4 ACM, changes in plasma membrane lipid rafts were investigated by staining for cholera toxin B. Methyl-b-cyclodextrin (MβCD) was applied to deplete cholesterol in ApoE4 ACM.Results: Secretory factors in conditioned media from hiPSC-derived astrocytes carrying APOE4 significantly increased the levels of APP and Aβ secretion in hiPSC-derived neurons. Increasing cholesterol levels in culture media mimicked the effects of ApoE4 ACM by inducing the formation of lipid rafts that potentially provide a physical platform for APP localization on the membrane. We further found that reducing cholesterol levels in ApoE4 ACM with MβCD abolished its effects on neuronal lipid raft expansion and Aβ generation.Conclusions: Our study suggests that ApoE4 astrocytes contribute to amyloidosis by the expansion of lipid rafts and facilitate neuronal Ab production through oversupply of cholesterol.
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ApoE4 astrocytes show significant accumulation of cholesterol compared with ApoE3 astrocytes.
“we found a significant accumulation of cholesterol in ApoE4 astrocytes compared with ApoE3 astrocytes”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [17]
The Results section reports prior findings of intracellular cholesterol accumulation in ApoE4 astrocytes compared with isogenic ApoE3 astrocytes. It does not state that this difference was statistically significant; this paper’s own measurements concern cholesterol secreted into astrocyte-conditioned media, not accumulation within the astrocytes. No page number is available in our copy. (LLM, conf=0.82)
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Self-citation
- Authors
- Lee, S.-I., Jeong, W., Lim, H., Cho, S., Lee, H., Jang, Y., Cho, J., Bae, S., Lin, Y.-T., Tsai, L.-H., Moon, D. W., & Seo, J.
- Affiliations
- Daegu Gyeongbuk Institute of Science and Technology (KR)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Seo, Jinsoo
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 16
- Issue
- 9
- Pages
- 2128-2137
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC8452535
- OpenAlex
- W3194957691
- Cited by
- 105
- References
- 9
- Citations by year
- 2026: 21 · 2025: 15 · 2024: 19 · 2023: 25 · 2022: 23 · 2021: 2
- FWCI
- 10.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- POSCO TJ Park Foundation
- National Research Foundation
- Ministry of Science, ICT and Future Planning
- National Research Foundation of Korea (2018M3C7A1056275)
- National Institutes of Health
- National Institute on Aging (RF1AG062377)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, apolipoprotein E, astrocytes, Alzheimer's disease, amyloid-beta, cholesterol secretion, lipid rafts, amyloid precursor protein, conditioned medium, APP processing
- MeSH terms
- Alzheimer Disease, Astrocytes, Cell Communication, Cholesterol, Extracellular Space, Humans, Neurons, Biomarkers, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Culture Media, Conditioned, Membrane Microdomains, Apolipoprotein E4, Induced Pluripotent Stem Cells
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