Apolipoprotein E modulates Alzheimer's Aβ(1-42)-induced oxidative damage to synaptosomes in an allele-specific manner

Christopher M. Lauderback, Jaroslaw Kanski, Janna M. Hackett, Noboyo Maeda, Mark S. Kindy, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

Several functional differences have been reported among the three human e2, e3, and e4 alleles of apolipoprotein E (apoE). One functional difference lies in the antioxidant potential of these alleles; e4 has the poorest potential. Interestingly, e4 also correlates with increased oxidative damage in the Alzheimer's disease (AD) brain, which may explain why the inheritance of the e4 allele is a risk factor for the onset of AD. Beta-amyloid (Aβ) is also intimately involved in AD and promotes oxidative damage in vitro; therefore, we have examined the role of the different apoE alleles in modulating Aβ(1-42)-induced oxidation to synaptosomes. Measurement of specific markers of oxidation in synaptosomes isolated from mice that express one of the human apoE alleles indicates that Aβ-induced increases of these markers can be modulated by apoE in an allele-dependent manner (e2>e3>e4). Increases in reactive oxygen species formation and protein and lipid oxidation were always greatest in e4 synaptosomes as compared to e2 and e3 synaptosomes. Our data support the role of apoE as a modulator of Aβ toxicity and, consistent with the antioxidant potentials of the three alleles, suggest that the e4 allele may not be as effective in this role as the e2 or e3 alleles of apoE. These results are discussed with reference to mechanistic implications for neurodegeneration in the AD brain.

Original languageEnglish
Pages (from-to)90-97
Number of pages8
JournalBrain Research
Volume924
Issue number1
DOIs
StatePublished - Jan 4 2002

Bibliographical note

Funding Information:
This work was supported in part by grants from NIH (AG-10836; AG-05119; AG-12423) to D.A.B. and (AG-12981; NS-32221) to M.S.K.

Keywords

  • 4-Hydroxynonenal
  • Apolipoprotein E
  • Beta-amyloid
  • Electron paramagnetic resonance
  • Lipid peroxidation
  • Oxidative stress
  • Protein oxidation

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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