Apolipoprotein E and low-density lipoprotein binding and internalization in primary cultures of rat astrocytes: Isoform-specific alterations

Daniel Guillaume, Philippe Bertrand, Doris Dea, Jean Davignon, Judes Poirier

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Apolipoprotein (apo) E is likely involved in redistributing cholesterol and phospholipids during compensatory synaptogenesis in the injured CNS. Three common isoforms of apoE exist in human (E2, E3, and E4). The apoE4 allele frequency is markedly increased in both late-onset sporadic and familial Alzheimer's disease (AD). ApoE concentration in the brain of AD subjects follows a gradient: ApoE levels decrease as a function of E2 > E3 >> E4. It has been proposed that the poor reinnervation capacity reported in AD may be caused by impairment of the apoE/low-density lipoprotein (LDL) receptor activity. To understand further the role of this particular axis in lipid homeostasis in the CNS, we have characterized binding, internalization, and degradation of human 125I-LDL to primary cultures of rat astrocytes. Specific binding was saturable, with a K(D) of 1.8 nM and a B(max) of 0.14 pmol/mg of proteins. Excess unlabeled human LDL or very LDL (VLDL) displaced 70% of total binding. Studies at 37°C confirmed that astrocytes bind, internalize, and degrade 125I-LDL by a specific, saturable mechanism. Reconstituted apoE (E2, E3, and E4)-liposomes were labeled with 125I and incubated with primary cultures of rat astrocytes and hippocampal neurons to examine specific binding. Human LDL and VLDL displaced binding and internalization of all apoE isoforms similarly in both astrocytes and neurons. 125I-ApoE2 binding was significantly lower than that of the other 125I-apoE isoforms in both cell types. 125I-ApoE4 binding was similar to that of 125I-apoE3 in both astrocytes and neurons. On the other hand, 125I-apoE3 binding was significantly higher in neurons than in astrocytes. These isoform-specific alterations in apoE-lipoprotein pathway could explain some of the differences reported in the pathophysiology of AD subjects carrying different apoE alleles.

Original languageEnglish (US)
Pages (from-to)2410-2418
Number of pages9
JournalJournal of Neurochemistry
Volume66
Issue number6
DOIs
StatePublished - Jun 1996
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Astrocyte
  • CNS
  • Cholesterol
  • Low-density lipoprotein receptor
  • Plasticity

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