Mechanism underlying apolipoprotein E (ApoE) isoform‐dependent lipid efflux from neural cells in culture
- 26 March 2009
- journal article
- research article
- Published by Wiley in Journal of Neuroscience Research
- Vol. 87 (11), 2498-2508
- https://doi.org/10.1002/jnr.22073
Abstract
We determined the molecular mechanisms underlying apolipoprotein E (ApoE)‐isoform‐dependent lipid efflux from neurons and ApoE‐deficient astrocytes in culture. The ability of ApoE3 to induce lipid efflux was 2.5‐ to 3.9‐fold greater than ApoE4. To explore the contributions of the amino‐ and carboxyl‐terminal tertiary structure domains of ApoE to cellular lipid efflux, each domain was studied separately. The amino‐terminal fragment of ApoE3 (22‐kDa‐ApoE3) induced lipid efflux greater than 22‐kDa‐ApoE4, whereas the common carboxyl‐terminal fragment of ApoE induced very low levels of lipid efflux. Addition of segments of the carboxyl‐terminal domain to 22‐kDa‐ApoE3 additively induced lipid efflux in a length‐dependent manner; in contrast, this effect did not occur with ApoE4. This observation, coupled with the fact that introduction of the E255A mutation (which disrupts domain–domain interaction) into ApoE4 increases lipid efflux, indicates that interaction between the amino‐ and carboxyl‐terminal domains in ApoE4 reduces the ability of this isoform to mediate lipid efflux from neural cells. Dimeric 22‐kDa or intact ApoE3 induced higher lipid efflux than monomeric 22‐kDa or intact ApoE3, respectively, indicating that dimerization of ApoE3 enhances the ability to release lipids. The adenosine triphosphate–binding cassette protein A1 (ABCA1) is involved in ApoE‐induced lipid efflux. In conclusion, there are two major factors, intramolecular domain interaction and intermolecular dimerization, that cause ApoE‐isoform‐dependent lipid efflux from neural cells in culture.Keywords
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