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Unique Lipoproteins Secreted by Primary Astrocytes From Wild Type, apoE (−/−), and Human apoE Transgenic Mice
Open accessAbstract
Composition of central nervous system lipoproteins affects the metabolism of lipoprotein constituents within the brain. The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease via an unknown mechanism(s). As glia are the primary central nervous system cell type that synthesize apoE, we characterized lipoproteins secreted by astrocytes from wild type (WT), apoE (-/-), and apoE transgenic mice expressing human apoE3 or apoE4 in a mouse apoE (-/-) background. Nondenaturing size exclusion chromatography demonstrates that WT, apoE3, and apoE4 astrocytes secrete particles the size of plasma high density lipoprotein (HDL) composed of phospholipid, free cholesterol, and protein, primarily apoE and apoJ. However, the lipid:apoE ratio of particles containing human apoE is significantly lower than WT. ApoE localizes across HDL-like particle sizes. ApoJ localizes to the smallest HDL-like particles. ApoE (-/-) astrocytes secrete little phospholipid or free cholesterol despite comparable apoJ expression, suggesting that apoE is required for normal secretion of astrocyte lipoproteins. Further, particles were not detected in apoE (-/-) samples by electron microscopy. Nondenaturing immunoprecipitation experiments indicate that apoE and apoJ reside predominantly on distinct particles. These studies suggest that apoE expression influences the unique structure of astrocyte lipoproteins, a process further modified by apoE species.
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“apoE4-lipoproteins are poorly lipidated compared to apoE3-lipoproteins.”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [22]
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“M-apoE and h-apoE differ in both structure [119] and functions ranging from lipid binding and transport, to effects on AD pathology [22, 84, 85, 119, 120].”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [22]
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“Astrocytes secrete ApoE in a similar size ranging from 8 to 20 nm [17, 19, 20].”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Generation of discoidal ApoE using recombinant protein and lipidation with lipids such as 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and dimyristoylphosphatidylcholine (DMPC) result in the formation of discoidal lipoprotein similar in diameter and conformation to astrocyte secreted human LpE [20, 56].”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [20]
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“In the central nervous system (CNS), ApoE is primarily secreted by astrocytes under homeostatic conditions with microglia upregulating ApoE secretion under multiple disease conditions [18–20, 93–95].”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [20]
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“Astrocytes with human APOE isoforms knocked into the endogenous mouse Apoe allele secrete discoidal particles of overlapping size.”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [20]
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“Nondenaturing PAGE reveals that the ApoE lipoprotein remains lipidated following immunopurification in line with previous reports (1, 49).”
From Lipidome and proteome of astrocyte and microglia ApoE lipoprotein reveal differences based on cell type and ApoE isoform (2026) · cites this paper as [1]
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“In the CNS, ApoE is initially secreted as a discoidal particle that is similar in size to HDL in plasma (1, 2, 49).”
From Lipidome and proteome of astrocyte and microglia ApoE lipoprotein reveal differences based on cell type and ApoE isoform (2026) · cites this paper as [1]
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“Under homeostatic conditions, ApoE is primarily produced by astrocytes which secrete lipidated ApoE [17–20].”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [20]
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“ApoE is the dominant constituent of the isolated ApoE lipoproteins, as expected (1, 2).”
From Lipidome and proteome of astrocyte and microglia ApoE lipoprotein reveal differences based on cell type and ApoE isoform (2026) · cites this paper as [1]
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“However, ApoE2 lipoproteins secreted from astrocytes form slightly larger particles than ApoE3 and ApoE4 lipoproteins [17–20].”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [20]
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“we found ApoE and ApoJ in HDL-like fractions, with an increase in ApoJ concentration within HDL-like fractions (Extended Data Figure 4)11.”
From Neurotoxic reactive astrocytes induce cell death via saturated lipids (2021) · cites this paper as [11]
In the citing paper
“Consistent with the hypothesis that ApoE and ApoJ are predominantly secreted in lipidated lipoparticles, we found ApoE and ApoJ in HDL-like fractions”
From Neurotoxic reactive astrocytes induce cell death via saturated lipids (2021) · cites this paper as [11]
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Metadata
- Authors
- Fagan, A. M., Holtzman, D. M., Munson, G., Mathur, T., Schneider, D., Chang, L. K., Getz, G. S., Reardon, C. A., Lukens, J., Shah, J. A., & LaDu, M. J.
- Affiliations
- Washington University in St. Louis (US)
- University of Chicago (US)
- Corresponding author
- Fagan, Anne M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-10
- Volume
- 274
- Issue
- 42
- Pages
- 30001-30007
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2163481458
- Cited by
- 222
- References
- 70
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 11 · 2023: 5 · 2022: 12 · 2021: 5 · 2020: 12 · 2019: 7 · 2018: 3 · 2017: 6 · 2016: 11 · 2015: 12 · 2014: 11 · 2013: 4 · 2012: 5
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (AG05681, AG13956)
- American Health Assistance Foundation
- University of Missouri
- National Institutes of Health (AG05681, AG13956)
- National Institute on Aging (R01AG013956, AG00861-01, AG05681-16, P50AG005681, AG13956)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, astrocytes, lipoprotein secretion, clusterin, APOE ε4, APOE3, ApoE-deficient mice, Alzheimer's disease risk, free cholesterol, phospholipids
- MeSH terms
- Animals, Apolipoproteins E, Astrocytes, Cells, Cultured, Chromatography, Gel, Electrophoresis, Polyacrylamide Gel, Humans, Lipoproteins, Mice, Transgenic, Microscopy, Electron, Mice
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