Alzheimer?s disease (AD) is an extremely important problem with devastating effects on elderly, presently affecting over 5 million persons in the United States. The number of persons with AD is projected to rise dramatically over the next several decades, creating an enormous public health and financial crisis. Thus far, the therapeutic strategies derived from mouse models of AD have universally failed in clinical trials. It has become apparent that the mouse models of AD do not adequately represent the salient features and risk factors associated with AD development and likely then, may not be able to deliver translational products from their studies. Here we propose to develop a model for the study of AD in rhesus macaques. Non human primates such as rhesus macaques and African Green monkeys do develop AD, naturally, with advance aging, unlike mice, however the paucity of such aged animals currently precludes their utility fir AD study. Here we investigate the hypothesis that nicotinamide adenine dinucleotide (NAD+) controls aging, protects against AD, however declines with age. Here we propose to investigate NAD+, and related process and metabolites involved in aging, early development of Alzheimer?s disease, including NAD+ metabolism, insulin resistance, and additional mechanisms involved in AD pathogenesis such as platelet activation and the kynurenine pathway in the context of normal aging in male and female macaques across the life span. We will further determine the ability of the anti-cancer drug, FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT or visfatin) a rate limiting step in NAD+ synthesis, to deplete NAD+ in rhesus macaques. We anticipate that this approach will lead to the acceleration of aging, reveal features of Alzheimer?s and facilitate future studies regarding AD pathogenesis and therapeutics development in this animal model. Our approach represents a fairly thorough interrogation of this hypothesis, involving the investigation of analytes associated with AD development, imaging studies, transcriptomics, and immunohistochemical studies.
An animal model for the study of Alzheimer?s disease treatment is urgently needed that replicates the salient features of the diseases and can be used to develop therapies that will actually prevent or treat this disease. This application is designed to establish such a model, by interfering with a pathway that would otherwise protect against aging. Our approach will investigate effects of this treatment on markers of aging and Alzheimer?s disease.
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