Alzheimer's disease (AD), the predominant dementing disorder of the elderly, is associated with oxidative stress, caused, in part, by the action of amyloid ?-peptide, and manifested by, among other indices, increased protein oxidation (1,2). We hypothesized that identity of specifically oxidized proteins in AD brain would lead to greater understanding of molecular mechanisms by which neurodegeneration occurs in this disorder. Accordingly, using AD brain obtained under the Rapid Autopsy Program of the University of Kentucky Alzheimer's Disease Research Center (PMI < 4 h), we performed proteomics analysis to identify proteins posttranslationally modified by increased protein carbonyls or 3-nitrotyrosine (3-10). Proteins that are oxidatively modified in AD brain are consistent with known biochemical or morphological alterations in this disorder. Among those proteins that are oxidatively modified in AD brain are those related to energy dysfunction [creatine kinase; ?-enolase; triosephosphate isomerase]. Lower levels of ATP, consistent with altered PET results of AD brain (11), impair numerous processes, including those needed to maintain the cell potential, the loss of which leads to excess intraneuronal Ca2+ accumulation and subsequent neuronal death. Other proteins that are oxidized in AD brain deal with excitotoxic mechanisms [glutamine synthetase; excitatory amino acid transporter 2]. Both these enzymes were previously reported to be of lower activity in AD brain (1,2), and now it is known why: the proteins are oxidatively modified. Their dysfunction could lead to excess extracellular glutamate, with consequent stimulation of the NMDA receptor and excitotoxic consequences to the neuron. Another class of proteins that is oxidatively modified in AD brain deals with the known dysfunction of the proteasome [ubiquitin carboxyl terminal hydrolase L-1, UCH L-1], whose function is to remove polyubiquitin from aggregated or damaged proteins to form monomeric ubiquitin prior to insertion of such proteins into the pore of the multicatalytic proteasome. Loss of activity of this protein would lead to excess ubiquitinylation of proteins, loss of activity of the proteasome, and accumulation of aggregated and damaged proteins. Each of these expectations is found in AD, and proteasomal dysfunction is a known method to causing neuronal death (12). Interestingly, proteomics analysis of a mouse with non-functional UCH L-1, which leads to A? deposition and neuronal loss, identified key oxidized proteins (13). A fourth class of proteins this is oxidized in AD brain deals with cholinergic function and phospholipid asymmetry [neuropolypeptide h3]. Dysfunction of this protein due to oxidative modification could lead to loss of phospholipid asymmetry, with consequent exposure of PS on the outer lipid lamellae, a signal for apoptosis. The final class of proteins that are oxidatively modified in AD brain is related to neurite length [dihydroprymindinase related protein 2]. Dysfunction of this protein due to oxidative modification would lead to shortening of neuritic lengths, observed in AD brain (14). A subsequent prediction would be decreased interneuronal communication, possibly important in a disease associated with memory loss.
Thus, proteomics analysis had led to new insights into potential mechanisms for neuronal loss in AD brain. Support: grants from the National Institute on Aging.
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