Oxidative stress in brain in mild cognitive impairment and early Alzheimer's disease: Implications for the progression of Alzheimer's disease.

摘要

The studies presented in this dissertation were conducted with the main focus of gaining a greater knowledge of the role of protein oxidation and oxidative stress in mild cognitive impairment and early Alzheimer's disease and the implications for the advancement of Alzheimer's disease. Aging is the course of chronological changes associated with the increased probability of non-disease- or injury- associated death. The immune and central nervous systems are greatly depressed as age increases, and cognitive decline is a consequence of central nervous system impairment. Age-related memory loss, even in minor instances, is inevitable in aging. Age is in fact a risk factor for several neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In particular, AD often begins as mild cognitive impairment (MCI), soon evolving to early Alzheimer's disease (EAD), and finally culminating to late-stage AD. However, the mechanisms for this progression are still unknown. Early diagnosis of AD is critical for proper treatment. As a corollary, diagnosis of MCI, arguably the earliest form of Alzheimer's disease, would give clinicians greater opportunity to delay disease progression through treatment.; Protein oxidation results from the interaction of proteins with reactive oxygen/nitrogen species (ROS/RNS) that can lead to cellular damage and elevated oxidative stress. Protein oxidation can occur through many different avenues including, but not limited to, protein nitration, carbonylation and 4-hydroxynonenal modification. Increased oxidative stress has been demonstrated in neurodegenerative diseases including MCI, AD, and PD. In this dissertation, the mechanisms of protein nitration and HNE-bound protein oxidation in MCI and EAD were investigated using a proteomics approach. Glycolytic enzymes were found to be reduced in disease compare to control correlating to altered metabolism observed in AD. Hippocampus and inferior parietal lobule (IPL) were used as regions of interest, since hippocampus is greatly affected in AD, and IPL is associated with reasoning, memory, and thought, which are also affected in AD. A differential analysis to better understand EAD protein expression was performed as well. Proteomics data showed an increase in protein oxidative modification (nitration and HNE modification) of specific proteins involved in energy metabolism, signal transduction, detoxification, and neuronal communication. Several of these proteins were found to be oxidatively modified throughout the three disease stages of AD, giving more insights into protein oxidation and oxidative stress in the progression of AD, potential biomarkers, and possible therapeutic strategies for this dementing disease. These protein modifications can greatly depress the protein's functionality and can ultimately lead to loss of function.; Taken together, these findings support the role of oxidative stress, protein nitration, and HNE modification in MCI and EAD. These studies show that there are oxidative/nitrosative modifications of specific brain proteins exist in MCI, EAD, and AD, some of which are in common across the spectrum of AD. Also, this dissertation research strongly suggests that alterations in energy metabolism, neuronal communication, signal transduction, and detoxification are involved in the progression of AD.; Keywords: Mild cognitive impairment, early Alzheimer's disease, oxidative stress, Proteomics, aging