Proteomic identification of specific oxidized proteins in ApoE-knockout mice: relevance to Alzheimer's disease.
We have examined oxidized proteins in the brain regions of wild-type (WT) and ApoE-knockout (KO) animals. Total protein oxidation in the hippocampus of young-KO (6 month) animals was approximately 2-fold greater than that of young-WT (6 month) animals and was similar to that of old-WT (18 month) and old-KO (18 month) animals. In the cortex of the same animals, the levels of total protein oxidation in all four groups were not significantly different. Two-dimensional electrophoresis (2-DE) coupled with immunostaining for protein carbonylation revealed six specific oxidation-sensitive proteins, the oxidation levels of which were increased in young-KO, old-WT, and old-KO mice compared with young-WT mice. These six oxidation-sensitive proteins were identified by mass spectrometry as glial fibrillary acidic protein, creatine kinase BB, disulfide isomerase, chaperonin subunit 5, dihydropyrimidase-related protein 2, and mortalin. These results indicate that the ApoE gene product offers protection against age-associated oxidative damage in the brain. Moreover, two of these proteins, creatine kinase and dihydropyrimidase-related protein 2, have recently been found to be oxidized in the brains of human subjects with Alzheimer's disease [Aksenov et al. J. Neurochem. 74: 2520-2527; 2000; Castegna et al. J. Neurochem. 82: 1524-1532; 2002]. These data suggest that the ApoE-knockout mouse serves as an appropriate model for studying pathogenic oxidative mechanisms influencing risk and progression of Alzheimer's disease.
Choi
Joungil
J
Molecular Aging Unit, Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Forster
Michael J
MJ
McDonald
Shelley R
SR
Weintraub
Susan T
ST
Carroll
Christopher A
CA
Gracy
Robert W
RW
D000375:Aging / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D001057:Apolipoproteins E; D009419:Nerve Tissue Proteins