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

• Published in: Neurobiology of Aging 2002-09, Vol.23 (5), p.655-664
• Main Authors: Allan Butterfield, D, Castegna, Alessandra, Lauderback, Christopher M, Drake, Jennifer
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid β-peptide; APOE; Biological and medical sciences; Cell Death; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Humans; Lipid Peroxidation; Medical sciences; Neurology; Neurons - metabolism; Neurons - pathology
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/S0197-4580(01)00340-2

Amyloid β-peptide [Aβ(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. Aβ(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, Aβ 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 4 h PMI, showed selective proteins are oxidatively modified in the AD brain. Creatine kinase (CK) and β-actin have increased carbonyl groups, and Glt-1, a glutamate transporter, has increased binding of HNE in AD. Aβ(1–42) addition to synaptosomes also results in HNE binding to Glt-1, thereby coupling increased Aβ(1–42) in AD brain to increased lipid peroxidation and its sequelae and possibly explaining the mechanism of glutatmate transport inhibition known in AD brain. Aβ 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 Aβ-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 Aβ(1–42)-induced oxidative stress, with APOE4 more vulnerable to Aβ(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 Aβ(1–42) and postmortem studies of lipid peroxidation (and its sequelae) in AD brain may help explain the APOE allele-relate