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Apolipoprotein E (ApoE) Isoform-dependent Lipid Release from Astrocytes Prepared from Human ApoE3 and ApoE4 Knock-in Mice
Open accessAbstract
We have reported previously (Michikawa, M., Fan, Q.-W., Isobe, I., and Yanagisawa, K. (2000) J. Neurochem. 74, 1008-1016) that exogenously added recombinant human apolipoprotein E (apoE) promotes cholesterol release in an isoform-dependent manner. However, the molecular mechanism underlying this isoform-dependent promotion of cholesterol release remains undetermined. In this study, we demonstrate that the cholesterol release is mediated by endogenously synthesized and secreted apoE isoforms and clarify the mechanism underlying this apoE isoform-dependent cholesterol release using cultured astrocytes prepared from human apoE3 and apoE4 knock-in mice. Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. The amount of cholesterol released into the culture media from the apoE3-expressing astrocytes was approximately 2.5-fold greater than that from apoE4-expressing astrocytes. In contrast, the amount of apoE3 released in association with the HDL-like particles was similar to that of apoE4, and the sizes of the HDL-like particles released from apoE3- and apoE4-expressing astrocytes were similar. The molar ratios of cholesterol to apoE in the HDL fraction of the culture media of apoE3- and apoE4-expressing astrocytes were 250 +/- 6.0 and 119 +/- 5.1, respectively. These data indicate that apoE3 has an ability to generate similarly sized lipid particles with less number of apoE molecules than apoE4, suggesting that apoE3-expressing astrocytes can supply more cholesterol to neurons than apoE4-expressing astrocytes. These findings provide a new insight into the issue concerning the putative alteration of apoE-related cholesterol metabolism in Alzheimer's disease.
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“In the central nervous system (CNS), apoE is mainly secreted by astrocytes, with different isoforms playing distinct roles in lipid metabolism and nervous system homeostasis [11, 12].”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [12]
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“Previous studies identified APOE-isoform specific effects on cholesterol flux and APOE levels in rodent brain cells and human periphery (Gong et al., 2002; Huang et al., 1995; Michikawa et al., 2000).”
From Cholesterol and matrisome pathways dysregulated in astrocytes and microglia (2022) · cites this paper as Gong et al., 2002
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“cholesterol release is reduced in primary glial cultures from apoE-TR mice expressing apoE4 compared with glial cells expressing apoE3 (35,73).”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [73]
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“apoE4 proteins are poorly lipidated and display an impaired capacity in lipid transport when compared to apoE3 proteins”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Gong et al 2002
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“While APOE mRNA levels were unchanged in mouse (Gong et al., 2002)”
From Cholesterol and matrisome pathways dysregulated in astrocytes and microglia (2022) · cites this paper as Gong et al., 2002
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Metadata
- Authors
- Gong, J.-S., Kobayashi, M., Hayashi, H., Zou, K., Sawamura, N., Fujita, S. C., Yanagisawa, K., & Michikawa, M.
- Affiliations
- Japan Society for the Promotion of Science (JP)
- Corresponding author
- Michikawa, Makoto
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 277
- Issue
- 33
- Pages
- 29919-29926
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2087083058
- Cited by
- 214
- References
- 68
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 8 · 2023: 4 · 2022: 10 · 2021: 10 · 2020: 11 · 2019: 13 · 2018: 6 · 2017: 3 · 2016: 8 · 2015: 6 · 2014: 7 · 2013: 9 · 2012: 6
- FWCI
- 10.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, APOE isoforms, APOE3, APOE ε4, astrocytes, lipid secretion, clusterin, cholesterol metabolism, Alzheimer's disease
- MeSH terms
- Animals, Apolipoproteins E, Astrocytes, Cells, Cultured, Humans, Protein Isoforms, Lipid Metabolism, Mice, Apolipoprotein E3, Apolipoprotein E4
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