ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes
Open accessAbstract
The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE protein aggregation plays a central role in AD pathology, including the accumulation of β-amyloid (Aβ). Lipid-poor ApoE4 protein is prone to aggregate and lipidating ApoE4 protects it from aggregation. The mechanisms regulating ApoE4 aggregation in vivo are surprisingly not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). ABCA1 recycling and degradation is regulated by ADP-ribosylation factor 6 (ARF6). We found that ApoE4 promoted greater expression of ARF6 compared with ApoE3, trapping ABCA1 in late-endosomes and impairing its recycling to the cell membrane. This was associated with lower ABCA1-mediated cholesterol efflux activity, a greater percentage of lipid-free ApoE particles, and lower Aβ degradation capacity. Human CSF from APOE ε4/ε4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF from APOE ε3/ε3 carriers. Enhancing ABCA1 activity rescued impaired Aβ degradation in ApoE4-treated cells and reduced both ApoE and ABCA1 aggregation in the hippocampus of male ApoE4-targeted replacement mice. Together, our data demonstrate that aggregated and lipid-poor ApoE4 increases ABCA1 aggregation and decreases ABCA1 cell membrane recycling. Enhancing ABCA1 activity to reduce ApoE and ABCA1 aggregation is a potential therapeutic strategy for the prevention of ApoE4 aggregation-driven pathology. SIGNIFICANCE STATEMENT ApoE protein plays a key role in the formation of amyloid plaques, a hallmark of Alzheimer's disease (AD). ApoE4 is more aggregated and hypolipidated compared with ApoE3, but whether enhancing ApoE lipidation in vivo can reverse ApoE aggregation is not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). In this study, we demonstrated that the greater propensity of lipid-poor ApoE4 to aggregate decreased ABCA1 membrane recycling and its ability to lipidate ApoE. Importantly, enhancing ABCA1 activity to lipidate ApoE reduced ApoE and ABCA1 aggregation. This work provides critical insights into the interactions among ABCA1, ApoE lipidation and aggregation, and underscores the promise of stabilizing ABCA1 activity to prevent ApoE-driven aggregation pathology.
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ABCA1 is the main cholesterol efflux transporter in astrocytes and transfers cellular cholesterol and phospholipids onto lipid-poor apolipoproteins.
“The main cholesterol efflux transporter in astrocytes is ATP-binding cassette transporter A1 (ABCA1), which transfers cellular cholesterol and PLs onto lipid-poor apolipoproteins that shuttle cholesterol8–10.”
From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [8]
The section on ABCA1-mediated efflux says that a primary function of ABCA1 is to transport cholesterol and phospholipids to apolipoprotein acceptor particles. The Introduction describes cholesterol transfer into nascent ApoE, and the paper studies ABCA1-mediated efflux in astrocytes. Our copy does not establish the comparative claim that ABCA1 is the main cholesterol efflux transporter in astrocytes. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAPOE4-bound cholesterol, taken up by the cell, is released from the receptor in the late endosome or lysosome, and aggregation of APOE4 has been shown to cause endosomal congestion and dysfunction.
“APOE4-bound cholesterol, taken up by the cell, is released from the receptor in the late endosome or lysosome, and aggregation of APOE4 has been shown to cause endosomal congestion and dysfunction (Narayan et al., 2020; Nuriel et al., 2017; Rawat et al., 2019).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Rawat et al., 2019
The Discussion (page unavailable) describes aggregated ApoE4 in acidic endosomes as a possible mechanism for endosomal congestion and reports impaired ApoE4 recycling. It does not establish that aggregation causes endosomal congestion and dysfunction, or describe APOE4-bound cholesterol being released from a receptor in a late endosome or lysosome. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe induced ApoE was similarly lipidated with or without the SphK2 inhibitor.
“We found that the induced ApoE was similarly lipidated (41, 42), with or without the SphK2 inhibitor (Fig. 7A).”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [42]
The section ‘ApoE4 associates with lower ABCA1-mediated cholesterol efflux and ApoE lipidation’ describes ApoE lipidation and measures ApoE particle sizes in astrocyte-conditioned media. It does not test a SphK2 inhibitor or show that induced ApoE was similarly lipidated with and without one; the citing sentence points to its own Fig. 7A for that comparison. (LLM, conf=0.78)
Experimental — accuracy not yet measuredAPOE4 and ABCA1 co-aggregate, reducing ABCA1 recycling to the membrane.
“Another study showed that APOE4 and ABCA1 co-aggregate, reducing ABCA1 recycling to the membrane (Rawat et al., 2019).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Rawat et al., 2019
ApoE4-positive cells show reduced cholesterol transport function.
“with ApoE4-positive cells showing reduced function (Rawat et al., 2019; Yamazaki et al., 2019).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Rawat et al., 2019
Promotion of ApoE4 lipidation suppresses ApoE4-driven pathology.
“the promotion of ApoE4 lipidation suppresses ApoE4-driven pathology (42, 73)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [42]
APOE4 drives changes to lipid trafficking in primary mouse astrocytes.
“Another study found that APOE4 drives changes to lipid trafficking in primary mouse astrocytes 32 .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [32]
ABCA1 agonists decreased ApoE and ABCA1 aggregation in the hippocampus of ApoE4-targeted replacement mice.
“ABCA1 agonists also rescued impaired Aβ degradation in ApoE4 cells and further decreased ApoE and ABCA1 aggregation in the hippocampus of ApoE4-targeted replacement mice [88].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [88]
ABCA1 agonists rescued impaired Aβ degradation in ApoE4 cells.
“ABCA1 agonists also rescued impaired Aβ degradation in ApoE4 cells and further decreased ApoE and ABCA1 aggregation in the hippocampus of ApoE4-targeted replacement mice [88].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [88]
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- Authors
- Rawat, V., Wang, S., Sima, J., Bar, R., Liraz, O., Gundimeda, U., Parekh, T., Chan, J., Johansson, J. O., Tang, C., Chui, H. C., Harrington, M. G., Michaelson, D. M., & Yassine, H. N.
- Affiliations
- University of Southern California (US)
- Tel Aviv University (IL)
- University of Washington (US)
- Huntington Medical Research Institutes (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2019-10-22
- Volume
- 39
- Issue
- 48
- Pages
- 9611-9622
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6880458
- OpenAlex
- W2981813975
- Cited by
- 165
- References
- 16
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 22 · 2023: 38 · 2022: 28 · 2021: 22 · 2020: 11
- FWCI
- 10.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG055770, R21AG056518, P50AG005142, R01AG054434)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK048522)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- APOE ε4, ABCA1, Alzheimer's disease, ARF6, cholesterol efflux, astrocytes, amyloid beta degradation, CsF, amyloid plaques, APOE3
- MeSH terms
- ADP-Ribosylation Factor 6, Aged, Aged, 80 and over, Animals, Astrocytes, Cell Line, Transformed, Cell Membrane, Cells, Cultured, Female, Cricetinae, HeLa Cells, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Protein Binding, Protein Transport, Mice, Apolipoprotein E4, ATP Binding Cassette Transporter 1
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