Proteins in Human Brain Cortex Are Modified by Oxidation, Glycoxidation, and Lipoxidation

Abstract

Diverse oxidative pathways, such as direct oxidation of amino acids, glycoxidation, and lipoxidation could contribute to Alzheimer disease pathogenesis. A global survey for the amount of structurally characterized probes for these reactions is lacking and could overcome the lack of specificity derived from measurement of 2,4-dinitrophenylhydrazine reactive carbonyls. Consequently we analyzed (i) the presence and concentrations of glutamic and aminoadipic semialdehydes, N ⑀ -(carboxymethyl)-lysine, N ⑀ -(carboxyethyl)-lysine, and N ⑀ -(malondialdehyde)-lysine by means of gas chromatography/mass spectrometry, (ii) the biological response through expression of the receptor for advanced glycation end products, (iii) the fatty acid composition in brain samples from Alzheimer disease patients and agematched controls, and (iv) the targets of N ⑀ -(malondialdehyde)-lysine formation in brain cortex by proteomic techniques. Alzheimer disease was associated with significant, although heterogeneous, increases in the concentrations of all evaluated markers. Alzheimer disease samples presented increases in expression of the receptor for advanced glycation end products with high molecular heterogeneity. Samples from Alzheimer disease patients also showed content of docosahexaenoic acid, which increased lipid peroxidizability. In accordance, N ⑀ -(malondialdehyde)-lysine formation targeted important proteins for both glial and neuronal homeostasis such as neurofilament L, ␣-tubulin, glial fibrillary acidic protein, ubiquinol-cytochrome c reductase complex protein I, and the ␤ chain of ATP synthase. These data support an important role for lipid peroxidationderived protein modifications in Alzheimer disease pathogenesis.

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

“…We also showed that the levels of MDA-modified vimentin increased as SAMP8 mice age, and this increase was coupled to a decrease in IgMs against vimentin and MDA. Athough MDA-modified vimentin was previously identified in the brain cortex of Alzheimer's patients via a proteomic screen of MDA-oxidized proteins (45), astrocytes in the brain demonstrate age-related changes that resemble those of the SASP, including expression of several cytokines, accumulation of proteotoxic aggregates, and elevated levels of vimentin (96). Nonetheless, the accumulation of MDA-modified vimentin detected in SAMP8 mice may also reflect senescence-independent cellular changes in response to DNA-damage signaling constitutively occurring in this mouse strain (97).…”

“…Vimentin was previously found to be modified by MDA in the human brain cortex of Alzheimer's patients and by CML in skin fibroblasts isolated from elderly donors and exposed to UV light (44,45). Given that vimentin is the target of various posttranslational modifications that include oxidation (46,47), we thus examined whether these oxidative adducts were associated with vimentin exposed on the surface of senescent cells.…”

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

“…This increased β-amyloid protein -induced oxidative stress in conjunction with decreased neurotrophic support [17] are the major determinants of AD. Studies undertaken in post-mortem brain samples obtained from AD patients have shown extensive lipid, protein and DNA oxidation [7]. Neural tissues of AD patients exhibit increased levels of peroxidation end-products such as malondialdehyde (MDA), 4-hydroxynonenal, carbonyls and other species [18].…”

“…Increased protein, lipid and DNA oxidation has been demonstrated in brain samples of AD patients [6]. Protein carbonyl 3, 3'-dityrosine and 3-nitrotyrosine levels in post-mortem brain samples of AD patients exhibit increased oxidative and nitrosative protein modification in the hippocampal and neocortical regions [7].…”

Proteomics‐driven progress in neurodegeneration research

“…There are hundreds of oxidized proteins in the brain; exist qualitative and quantitative differences between control and diseased brain [74,75], and proteomics represents a powerful approach to study protein oxidation [76]. In the AD brain, oxidation is observed in regions where amyloid b-peptide (Ab) 1-42 is present, but not in cerebellum where AD pathology is not observed [77,78].…”