Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease

Roy G. Cutler, Jeremiah Kelly, Kristin Storie, Ward A. Pedersen, Anita Tammara, Kimmo Hatanpaa, Juan C. Troncoso, Mark P. Mattson

Research output: Contribution to journalArticle

689 Scopus citations

Abstract

Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid β-peptide (Aβ) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to Aβ deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to Aβ induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with α-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Aβ. Our findings suggest a sequence of events in the pathogenesis of AD in which Aβ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.

Original languageEnglish (US)
Pages (from-to)2070-2075
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number7
DOIs
StatePublished - Feb 17 2004

Keywords

  • Amyloid
  • Apoptosis
  • Hippocampus
  • Lipid peroxidation
  • Sphingomyelin

ASJC Scopus subject areas

  • General

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