No effective disease-modifying treatments currently exist for Alzheimer's disease (AD) and without such treatments, the number of individuals afflicted and the associated financial and caregiver burden will increase dramatically. To address this unmet medical and societal need, our research is focused on the development of drug treatments capable of preventing or slowing the progression of AD. Brain inflammation triggered by chronic stress is a proven component in the pathogenic cascade leading to mild cognitive impairment and AD. When the reactive inflammatory molecules nitric oxide and superoxide are in surplus they combine to form the brain-imparing reactive species peroxynitrite which perpetuates the inflammatory process leading to the progressive neurodegneration seen in AD. Our strategy is to break the cycle of peroxynitrite production observed in AD by selectively blocking the unsafe elevation of nitric oxide, a molecule required to form peroxynitrite. This will be accomplished by developing drugs that selectively target the S1R brain protein, because this protein regulates nitric oxide levels in brain cells experiencing high levels of inflammatory (oxidative) stress. We hypothesize that reducing excessive levels of nitric oxide in oxidatively-stressed brain cells will interfere with a molecular mechanism perpetuating AD-type neurodegeneration and thereby either halt or attenuate the progression of the disease. Fortuitously, the same S1R protein mediates the secretion of the natural brain substance brain-derived neurotrophic factor (BDNF) which promotes the growth of new neurons and strengthens the interconnections between them making the brain more resilient to inflammatory insults. Notably, cognitive decline is slower in AD patients with higher levels of BDNF, exercise promotes BNDF secretion and reduces the risk of AD, and genetic variations leading to lower levels of secreted BDNF are associated with an increased risk of AD, thus S1R protein regulation of BDNF secretion provides a second, and equally important, mechanism as an AD therapy.