Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease: Implications for Aβ accumulation in AD brain

Joshua B. Owen, Rukhsana Sultana, Christopher D. Aluise, Michelle A. Erickson, Tulin O. Price, Guojun Bu, William A. Banks, D. Allan Butterfield

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Alzheimer disease (AD) is a neurodegenerative disorder characterized histopathologically by the presence of senile plaques (SPs), neurofibrillary tangles, and synapse loss. The main component of SPs is amyloid-β peptide (Aβ), which has been associated with increased oxidative stress, leading to oxidative modification of proteins and consequently to neurotoxicity and neurodegeneration. Low-density lipoprotein receptor-related protein 1 (LRP1) is the primary moiety responsible for the efflux of Aβ from the brain to the blood across the blood-brain barrier. Impaired brain-to-blood transport of Aβ by LRP1 has been hypothesized to contribute to increased levels of Aβ in AD brain. The cause of LRP1 dysfunction is unknown, but we have hypothesized that Aβ oxidizes LRP1, thus damaging its own transporter. Consistent with this notion, we report in this study a significant increase in the levels of the lipid peroxidation product 4-hydroxy-2-nonenal bound to transmembrane LRP1 in AD hippocampus. In contrast, the levels of LRP1-resident 3-nitrotyrosine did not show a significant increase in AD hippocampus compared to age-matched controls. Based on this study, we propose that Aβ impairs its own efflux from the brain by oxidation of its transporter LRP1, leading to increased Aβ deposition in brain, thereby contributing to subsequent cognitive impairment in AD.

Original languageEnglish (US)
Pages (from-to)1798-1803
Number of pages6
JournalFree Radical Biology and Medicine
Volume49
Issue number11
DOIs
StatePublished - Dec 1 2010

    Fingerprint

Keywords

  • 4-Hydroxy-2-nonenal
  • Alzheimer disease
  • Amyloid β-peptide
  • Free radicals
  • Lipid peroxidation
  • Low-density lipoprotein receptor-related protein 1
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this