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

DOI Web Site 17 Citations
  • Roy G. Cutler
    Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224; Rush Alzheimer's Disease Center, Rush–Presbyterian–St. Luke's Medical Center, 1645 West Jackson Street, Chicago, IL 60612; and Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
  • Jeremiah Kelly
    Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224; Rush Alzheimer's Disease Center, Rush–Presbyterian–St. Luke's Medical Center, 1645 West Jackson Street, Chicago, IL 60612; and Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
  • Kristin Storie
    Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224; Rush Alzheimer's Disease Center, Rush–Presbyterian–St. Luke's Medical Center, 1645 West Jackson Street, Chicago, IL 60612; and Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
  • Ward A. Pedersen
    Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224; Rush Alzheimer's Disease Center, Rush–Presbyterian–St. Luke's Medical Center, 1645 West Jackson Street, Chicago, IL 60612; and Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
  • Anita Tammara
    Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224; Rush Alzheimer's Disease Center, Rush–Presbyterian–St. Luke's Medical Center, 1645 West Jackson Street, Chicago, IL 60612; and Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
  • Kimmo Hatanpaa
    Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224; Rush Alzheimer's Disease Center, Rush–Presbyterian–St. Luke's Medical Center, 1645 West Jackson Street, Chicago, IL 60612; and Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
  • Juan C. Troncoso
    Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224; Rush Alzheimer's Disease Center, Rush–Presbyterian–St. Luke's Medical Center, 1645 West Jackson Street, Chicago, IL 60612; and Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
  • Mark P. Mattson
    Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224; Rush Alzheimer's Disease Center, Rush–Presbyterian–St. Luke's Medical Center, 1645 West Jackson Street, Chicago, IL 60612; and Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205

Description

<jats:p>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.</jats:p>

Journal

Citations (17)*help

See more

Details 詳細情報について

Report a problem

Back to top