Redox proteomics identification of specifically carbonylated proteins in the hippocampi of triple transgenic Alzheimer's disease mice at its earliest pathological stage

摘要

Alzheimer's disease (AD) is the most common cause of dementia in the elderly population. Attempts to develop therapies for the treatment of the late stage AD have been unsuccessful. Increasing evidences indicate that oxidative stress is an early event of neurodegeneration, however the pathogenic mechanism of AD remains unclarified. In the present study, slot-blot analysis was used to determine the levels of protein carbonyls in the hippocampi of 3-month-old triple transgenic AD mice (3 x Tg-AD). The increased levels of protein carbonyls were observed in the hippocampi of 3 x Tg-AD mice as compared to the non-transgenic controls (non-Tg). Using a redox-proteomic approach, twelve proteins were found to be significantly altered in the levels of protein carbonyls in the hippocampus. These proteins are crucial in energy metabolism, protein folding, cell structure, signal transduction and excitotoxicity. Immunoprecipitation and Western blot were used to validate two proteins identified by the redox proteomics. In addition, increased expression level of carbonyl reductase 1 (CBR1) was observed in the hippocampi of 3 x Tg-AD mice. These results demonstrate that significant protein carbonylation occurs early in the 3-month-old 3 x Tg-AD mice, which support the viewpoint that oxidative stress is an early event in AD progression.