Effects of oxidative and nitrosative stress in brain on p53 proapoptotic protein in amnestic mild cognitive impairment and Alzheimer disease

Abstract

Many studies reported that oxidative and nitrosative stress might be important for the pathogenesis of Alzheimer's disease (AD) beginning with arguably the earliest stage of AD, i.e., as mild cognitive impairment (MCI). p53 is a pro-apoptotic protein that plays an important role in neuronal death, a process involved in many neurodegenerative disorders. Moreover, p53 plays a key role in the oxidative stress-dependent apoptosis. We demonstrated previously that p53 levels in brain were significantly higher in MCI and AD IPL compared to control brains. In addition, we showed that in AD IPL, but not in MCI, HNE, a lipid peroxidation product, was significantly bound to p53 protein.In this report, we studied by means of immunoprecipitation analysis, the levels of markers of protein oxidation, 3-nitrotyrosine (3-NT) and protein carbonyls in p53 in a specific region of the cerebral cortex, namely the inferior parietal lobule (IPL), in MCI and AD compared to control brains. The focus of these studies was to measure the oxidation and nitration status of this important pro-apoptotic protein, consistent with hypothesis that oxidative modification of p53 could be involved in the neuronal loss observed in neurodegenerative conditions.

Lack of p53 Decreases Basal Oxidative Stress Levels in the Brain Through Upregulation of Thioredoxin-1, Biliverdin Reductase-A, Manganese Superoxide Dismutase, and Nuclear Factor Kappa-B

“…1). As previously reported, even p53 represents a target for oxidative and nitrosative posttranslational modifications in MCI and AD (13,14). In particular, an increase of p53 protein levels was observed in MCI and AD brain compared with control samples (14), paralleled by an increase of oxidative/nitrosative modifications, which, in turn, could affect its activity (13,14).…”

Inhibition of erythropoiesis in malaria anemia: role of hemozoin and hemozoin-generated 4-hydroxynonenal

“…30 HNE may add to those covalent p53 modifiers. 33,34 In addition, HNE was shown to bind to guanine residues in DNA possibly generating a DNA-damage signal that may phosphorylate and stabilize p53. 35 As a first partial conclusion, above data may provide a mechanistic explanation on how HZ and HNE generated in the BM may slow down erythropoiesis and establish a causal link with malaria anemia.…”

Mechanisms of Altered Redox Regulation in Neurodegenerative Diseases—Focus on S-Glutathionylation

“…In regard to neurodegenerative diseases, p53 has been reported to be elevated both in mild cognitive impairment, in AD, and in PD (31, 120). Brain samples from AD patients showed increased oxidation of p53 compared to controls (31). More recently, p53 was found to be glutathionylated in samples from AD patients compared to age-matched controls.…”