Neurobiology of Aging 23 (2002) 655–664 Review Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death  D. Allan Butterfield ∗ , Alessandra Castegna, Christopher M. Lauderback, Jennifer Drake Department of Chemistry, Center of Membrane Sciences, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA Abstract Amyloid -peptide [A(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. A(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, A 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 -actin have increased carbonyl groups, and Glt-1, a glutamate transporter, has increased binding of HNE in AD. A(1–42) addition to synaptosomes also results in HNE binding to Glt-1, thereby coupling increased A(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. A 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 A-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 A(1–42)-induced oxidative stress, with APOE4 more vulnerable to A(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 A(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 A(1–42)-induced oxidative stress in AD neurodegeneration. Published by Elsevier Science Inc. Keywords: Amyloid -peptide; Alzheimer’s disease; APOE 1. Introduction Alzheimer’s disease (AD), the major dementing disor- der of the elderly, affects more than four million persons in the United States of America. Aging is the chief risk factor for AD. Major pathological hallmarks of AD include loss of synapses and the presence of senile plaques (SP) and neurofibrillary tangles (NFT). SP consist of a highly dense core of the 39–43 amino acid peptide, amyloid -peptide [A(1–42)], surrounded by dystrophic neurites [35]. Based  Invited submission to Neurobiology of Aging special issue associated with the conference on Brain Aging: Identifying Accelerators and Brakes. ∗ Corresponding author. Tel.: +1-859-257-3184; fax: +1-859-257-5876. E-mail address: dabcns@uky.edu (D. Allan Butterfield). primarily on genetic evidence, A likely is central to the pathogenesis of AD (reviewed in [87]). Further, the AD brain is under extensive oxidative stress indexed by protein oxida- tion, lipid peroxidation, DNA and RNA oxidation, advanced glycation endproducts, protein nitration, mitochondrial ab- normalities, reactive oxygen species (ROS) formation, and other markers (reviewed in [13,14,58]). The centrality of the 42-amino acid form of this peptide, A(1–42), to the pathogenesis of AD was coupled to the extensive oxidative stress under which the AD brain exists in the A-associated free radical oxidative stress model for neurodegeneration in AD brain [14,96]. In this model, A-associated free radicals cause oxidative stress, includ- ing lipid peroxidation, in ways that are inhibited by free radical scavengers. In this review, free radical induced lipid 0197-4580/02/$ – see front matter. Published by Elsevier Science Inc. PII:S0197-4580(01)00340-2