Redox proteomics analysis to decipher the neurobiology of Alzheimer-like neurodegeneration: overlaps in Down's syndrome and Alzheimer's disease brain

Accumulation of oxidative damage is a common feature of neurodegeneration that, together with mitochondrial dysfunction, point to the fact that reactive oxygen species are major contributors to loss of neuronal homoeostasis and cell death. Among several targets of oxidative stress, free-radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases. In the majority of cases, oxidative-stress-mediated post-translational modifications cause non-reversible modifications of protein structure that consistently lead to impaired function. Redox proteomics methods are powerful tools to unravel the complexity of neurodegeneration, by identifying brain proteins with oxidative post-translational modifications that are detrimental for protein function. The present review discusses the current literature showing evidence of impaired pathways linked to oxidative stress possibly involved in the neurodegenerative process leading to the development of Alzheimer-like dementia. In particular, we focus attention on dysregulated pathways that underlie neurodegeneration in both aging adults with DS (Down's syndrome) and AD (Alzheimer's disease). Since AD pathology is age-dependent in DS and shows similarities with AD, identification of common oxidized proteins by redox proteomics in both DS and AD can improve our understanding of the overlapping mechanisms that lead from normal aging to development of AD. The most relevant proteomics findings highlight that disturbance of protein homoeostasis and energy production are central mechanisms of neurodegeneration and overlap in aging DS and AD. Protein oxidation affects crucial intracellular functions and may be considered a ‘leitmotif’ of degenerating neurons. Therapeutic strategies aimed at preventing/reducing multiple components of processes leading to accumulation of oxidative damage will be critical in future studies. Abbreviations: Aβ, amyloid β peptide; AD, Alzheimer’s disease; AGE, advanced glycation end-product; APP, amyloid precursor protein; CAT, catalase; Chr21, chromosome 21; CMA, chaperone-mediated autophagy; 2,4-DNPH, 2,4-dinitrophenylhydrazine; DS, Down's syndrome; ER, endoplasmic reticulum; ETC, electron transport chain; FBA, fructose bisphosphate aldolase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein; GPX, glutathione peroxidase; GRP78, glucose-regulated protein of 78 kDa; HNE, 4-hydroxynonenal; HSC71, heat-shock cognate 71 stress protein; HSP, heat-shock protein; MAPK, mitogen-activated protein kinase; MCI, mild cognitive impairment; MDH, malate dehydrogenase; MeSOX, methionine sulfoxide; NFT, neurofibrillary tangle; 3-NT, 3-nitrotyrosine; OS, oxidative stress; PK, pyruvate kinase; PQC, protein quality control; PTM, post-translational modification; PUFA, polyunsaturated fatty acid; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, superoxide dismutase; TCA, tricarboxylic acid; UCH-L1, ubiquitin C-terminal hydrolase L1; UPR, unfolded protein response; UPS, ubiquitin–proteasome system