Endogenous metabolism and environmental exposure can give rise to DNA adduct formation. Multiple lines of evidence suggest that environmental exposure to alkylating agents is associated with increased incidence of neurodegenerative diseases, including Alzheimer?s Disease, in both animal models and in certain human population. In this Administrative Supplement in response to NOT-AG-18-008, we hypothesize that environmental exposure to alkylating agents and the ensuing formation of alkylated and oxidative stress-induced DNA adducts may contribute to the development and progression of Alzheimer's Disease. To test this hypothesis, we will employ state-of-the-art LC-MS/MS and MS/MS/MS methods to quantify the levels of alkylated DNA lesions and oxidative stress-induced DNA lesions in brain tissues of Alzheimer?s disease patients with different levels of disease severity (intermediate and high) and age-matched human subjects. The research proposed in this Administrative Supplement fits with the scope of the parent R01 (ES025121), which focuses on examining the occurrence, repair and biological consequences of alkylated DNA lesions. The outcome of the proposed research will provide important new knowledge for understanding the implications of exposure to alkylating agents and the resultant DNA adduct formation in the development of Alzheimer?s disease.
Humans are exposed to various alkylating agents present environmental exposure and produced by endogenous metabolism. The outcome of the research proposed in this Administrative Supplement will provide important new knowledge about the roles of DNA adducts induced from exposure to alkylating agents in the development and progression of Alzheimer?s disease.
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