Mechanism underlying apolipoprotein E (ApoE) isoform-dependent lipid efflux from neural cells in culture

J Neurosci Res. 2009 Aug 15;87(11):2498-508. doi: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Apolipoprotein E3 / genetics
  • Apolipoprotein E3 / metabolism*
  • Apolipoprotein E4 / genetics
  • Apolipoprotein E4 / metabolism*
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Brain / drug effects
  • Brain / metabolism
  • Cells, Cultured
  • Central Nervous System Agents / pharmacology
  • Cholesterol / metabolism*
  • Glyburide / pharmacology
  • Humans
  • Hydroxycholesterols / pharmacology
  • Mutation
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phosphatidylcholines / metabolism*
  • Protein Multimerization / physiology
  • Rats
  • Time Factors

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Central Nervous System Agents
  • Hydroxycholesterols
  • Phosphatidylcholines
  • 22-hydroxycholesterol
  • Cholesterol
  • Glyburide