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Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death.

Abstract

Amyloid beta-peptide [Abeta(1-42)] is central to the pathogenesis of Alzheimer's disease (AD), and the AD brain is under intense oxidative stress, including membrane lipid peroxidation. Abeta(1-42) causes oxidative stress in and neurotoxicity to neurons in mechanisms that are inhibited by Vitamin E and involve the single methionine residue of this peptide. In particular, Abeta induces lipid peroxidation in ways that are inhibited by free radical antioxidants. Two reactive products of lipid peroxidation are the alkenals, 4-hydroxynonenal (HNE) and 2-propenal (acrolein). These alkenals covalently bind to synaptosomal protein cysteine, histidine, and lysine residues by Michael addition to change protein conformation and function. HNE or acrolein binding to proteins introduces a carbonyl to the protein, making the protein oxidatively modified as a consequence of lipid peroxidation. Immunoprecipitation of proteins from AD and control brain, obtained no longer than 4h PMI, showed selective proteins are oxidatively modified in the AD brain. Creatine kinase (CK) and beta-actin have increased carbonyl groups, and Glt-1, a glutamate transporter, has increased binding of HNE in AD. Abeta(1-42) addition to synaptosomes also results in HNE binding to Glt-1, thereby coupling increased Abeta(1-42) in AD brain to increased lipid peroxidation and its sequelae and possibly explaining the mechanism of glutamate transport inhibition known in AD brain. Abeta also inhibits CK. Implications of these findings relate to decreased energy utilization, altered assembly of cytoskeletal proteins, and increased excitotoxicity to neurons by glutamate, all reported for AD. The epsilon-4 allele of the lipid carrier protein apolipoprotein E (APOE) allele is a risk factor for AD. Synaptosomes from APOE knock-out mice are more vulnerable to Abeta-induced oxidative stress (protein oxidation, lipid peroxidation, and ROS generation) than are those from wild-type mice. Further, synaptosomes from allele-specific APOE knock-in mice have tiered vulnerability to Abeta(1-42)-induced oxidative stress, with APOE4 more vulnerable to Abeta(1-42) than are those from APOE2 or APOE3 mice. These results are consistent with the notion of a coupling of the oxidative environment in AD brain and increased risk of developing this disorder. Taken together, the findings from in-vitro studies of lipid peroxidation induced by Abeta(1-42) and postmortem studies of lipid peroxidation (and its sequelae) in AD brain may help explain the APOE allele-related risk for AD, some of the functional and structural alterations in AD brain, and strongly support a causative role of Abeta(1-42)-induced oxidative stress in AD neurodegeneration.

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  • Authors+Show Affiliations

    ,

    Department of Chemistry, Center of Membrane Sciences, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA. dabcns@uky.edu

    , ,

    Source

    Neurobiology of aging 23:5 pg 655-64

    MeSH

    Aged
    Alzheimer Disease
    Amyloid beta-Peptides
    Cell Death
    Humans
    Lipid Peroxidation
    Neurons

    Pub Type(s)

    Journal Article
    Research Support, U.S. Gov't, P.H.S.
    Review

    Language

    eng

    PubMed ID

    12392766

    Citation

    Butterfield, D Allan, et al. "Evidence That Amyloid Beta-peptide-induced Lipid Peroxidation and Its Sequelae in Alzheimer's Disease Brain Contribute to Neuronal Death." Neurobiology of Aging, vol. 23, no. 5, 2002, pp. 655-64.
    Butterfield DA, Castegna A, Lauderback CM, et al. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death. Neurobiol Aging. 2002;23(5):655-64.
    Butterfield, D. A., Castegna, A., Lauderback, C. M., & Drake, J. (2002). Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death. Neurobiology of Aging, 23(5), pp. 655-64.
    Butterfield DA, et al. Evidence That Amyloid Beta-peptide-induced Lipid Peroxidation and Its Sequelae in Alzheimer's Disease Brain Contribute to Neuronal Death. Neurobiol Aging. 2002;23(5):655-64. PubMed PMID: 12392766.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death. AU - Butterfield,D Allan, AU - Castegna,Alessandra, AU - Lauderback,Christopher M, AU - Drake,Jennifer, PY - 2002/10/24/pubmed PY - 2003/1/11/medline PY - 2002/10/24/entrez SP - 655 EP - 64 JF - Neurobiology of aging JO - Neurobiol. Aging VL - 23 IS - 5 N2 - Amyloid beta-peptide [Abeta(1-42)] is central to the pathogenesis of Alzheimer's disease (AD), and the AD brain is under intense oxidative stress, including membrane lipid peroxidation. Abeta(1-42) causes oxidative stress in and neurotoxicity to neurons in mechanisms that are inhibited by Vitamin E and involve the single methionine residue of this peptide. In particular, Abeta induces lipid peroxidation in ways that are inhibited by free radical antioxidants. Two reactive products of lipid peroxidation are the alkenals, 4-hydroxynonenal (HNE) and 2-propenal (acrolein). These alkenals covalently bind to synaptosomal protein cysteine, histidine, and lysine residues by Michael addition to change protein conformation and function. HNE or acrolein binding to proteins introduces a carbonyl to the protein, making the protein oxidatively modified as a consequence of lipid peroxidation. Immunoprecipitation of proteins from AD and control brain, obtained no longer than 4h PMI, showed selective proteins are oxidatively modified in the AD brain. Creatine kinase (CK) and beta-actin have increased carbonyl groups, and Glt-1, a glutamate transporter, has increased binding of HNE in AD. Abeta(1-42) addition to synaptosomes also results in HNE binding to Glt-1, thereby coupling increased Abeta(1-42) in AD brain to increased lipid peroxidation and its sequelae and possibly explaining the mechanism of glutamate transport inhibition known in AD brain. Abeta also inhibits CK. Implications of these findings relate to decreased energy utilization, altered assembly of cytoskeletal proteins, and increased excitotoxicity to neurons by glutamate, all reported for AD. The epsilon-4 allele of the lipid carrier protein apolipoprotein E (APOE) allele is a risk factor for AD. Synaptosomes from APOE knock-out mice are more vulnerable to Abeta-induced oxidative stress (protein oxidation, lipid peroxidation, and ROS generation) than are those from wild-type mice. Further, synaptosomes from allele-specific APOE knock-in mice have tiered vulnerability to Abeta(1-42)-induced oxidative stress, with APOE4 more vulnerable to Abeta(1-42) than are those from APOE2 or APOE3 mice. These results are consistent with the notion of a coupling of the oxidative environment in AD brain and increased risk of developing this disorder. Taken together, the findings from in-vitro studies of lipid peroxidation induced by Abeta(1-42) and postmortem studies of lipid peroxidation (and its sequelae) in AD brain may help explain the APOE allele-related risk for AD, some of the functional and structural alterations in AD brain, and strongly support a causative role of Abeta(1-42)-induced oxidative stress in AD neurodegeneration. SN - 0197-4580 UR - https://www.unboundmedicine.com/medline/citation/12392766/Evidence_that_amyloid_beta_peptide_induced_lipid_peroxidation_and_its_sequelae_in_Alzheimer's_disease_brain_contribute_to_neuronal_death_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197458001003402 DB - PRIME DP - Unbound Medicine ER -