(Applicant s abstract) The deleterious effects of age-related neurodegenerative diseases are not only felt at the personal level but also as an ever-increasing financial burden on the national healthcare system. However, there is no cure or a preventive treatment currently available for neurodegenerative diseases such as Alzheimer's disease (AD). Elucidation of the mechanisms underlying selective neuronal death observed in AD may help conceptualize a new treatment or a therapeutic approach. Oxidative stress, though a culprit of neuronal death observed in AD and other neurodegenerative diseases, may also activate a survival response by regulating a subset of proteins and genes, resulting in selective protection of neurons. Characterization of such a survival response, therefore, is an important step toward prevention of neuronal death as well as promotion of neuronal survival. The central hypothesis of this proposal is that the activation of the signal transduction cascade involving phosphatidylinositol 3-OH kinases (PI3K) confers resistance to oxidative injury caused by amyloid beta (ABI-42), while the down regulation of this pathway by chronic exposure to AB results in neurodegeneration. In this context, the main objectives of this project is to define the role of PI3K cascade in neurodegeneration observed in AD by investigating the effects of AB on PI3K in a comprehensive multi-system which includes human brains with AD, APP transgenic mice, and neuronal cell cultures. During the course of the proposal, the applicant will receive additional training in clinical aspects of neuroscience such as neuropathology in the context of AD neurodegeneration. Also, with the aid of the sponsor and consultants, the applicant will obtain training in the transgenic mouse models, which can be used to test the above hypothesis as well as to develop therapies for treatment of age-related neurological disorders. Finally, the award will assist the applicant to become an independent faculty member actively involved in research in age-related neuro-degeneration as well as in teaching at a biomedical research institution such as UCSD.
