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Apolipoprotein E (ApoE) isoform-dependent lipid release from astrocytes prepared from human ApoE3 and ApoE4 knock-in
Jian-Sheng Gong1, Mariko Kobayashi, Hideki Hayashi
1Department of Dementia Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan.
Abstract:
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.
Insights
Apolipoprotein E (apoE) isoform 3 (apoE3) facilitates greater cholesterol release from astrocytes than apoE4. This suggests apoE3-expressing astrocytes may better supply cholesterol to neurons, impacting Alzheimer's disease research.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Previous research indicated exogenous apolipoprotein E (apoE) promotes cholesterol release in an isoform-dependent manner.
- The precise molecular mechanism behind apoE's isoform-dependent cholesterol release remained unclear.
Purpose of the Study:
- To investigate the mechanism of endogenous apoE isoform-dependent cholesterol release.
- To compare cholesterol release mediated by apoE3 and apoE4 isoforms in cultured astrocytes.
Main Methods:
- Utilized cultured astrocytes from human apoE3 and apoE4 knock-in mice.
- Analyzed cholesterol and phospholipid release into culture media.
- Characterized high-density lipoprotein (HDL)-like particles associated with apoE and apoJ.
Main Results:
- ApoE3-expressing astrocytes released approximately 2.5-fold more cholesterol than apoE4-expressing astrocytes.
- Similar amounts of apoE3 and apoE4 were released in association with HDL-like particles of comparable sizes.
- The molar ratio of cholesterol to apoE was significantly higher in apoE3-derived HDL-like particles compared to apoE4-derived ones.
Conclusions:
- ApoE3 generates larger cholesterol-carrying HDL-like particles with fewer apoE molecules than apoE4.
- ApoE3-expressing astrocytes demonstrate a superior capacity for cholesterol supply to neurons compared to apoE4-expressing astrocytes.
- Findings offer new insights into apoE-related cholesterol metabolism alterations in Alzheimer's disease.