This is a revised renewal application for a program projects grant entitled Excitatory Transmitters, Memory, Aging and Dementia (ETMAD), which has been funded for 4 years during which we have developed several strong lines of research that will serve as the foundation of this renewal proposal. A central theme of the proposal pertains to a neurodegenerative mechanism, NMDA receptor hypofunction (NRHypo), that we propose may play a key role in Alzheimer's disease (AD). A major emphasis of the proposed research is on testing certain tenets or predictions of the NRHYPO hypothesis. For example, we will induce an NRHYPO neurodegenerative reaction in the brains of transgenic mice to express beta amyloid to determine whether amyloidopathy and the NRHypo degenerative process interact to produce AD-like neuropathological changes and cognition deterioration. We will apply several approaches to address the question whether the neurodegenerative process in AD is mediated by an apoptotic mechanism, as many have proposed, or an excitotoxic mechanism, as our NRHYPO hypothesis proposes. We will explore preliminary evidence suggesting that estrogen may suppress NRHypo neurodegeneration, as it reportedly suppresses the neurodegenerative process in AD. We will follow up experiments to confirm our preliminary evidence to the NRHypo mechanism, and will conduct experiments to confirm our preliminary evidence that non-human primates are susceptible to the NRHypo neurodegenerative mechanism (an issue that currently is in dispute). The ultimate goal of these experiments is to develop a primate model for studying transmitter mechanisms potentially relevant to the pathophysiology of AD. To facilitate research in several projects pertaining to amyloidopathy or apoptosis we proposed to add a new core to the ETMAD program which will maintain a transgenic mouse facility to provide project leaders with transgenic or knockout mice that have genetic alterations relevant to the production or deposition of beta amyloid, or relevant to factors that promote or inhibit expression of apoptotic cell death. This new core facility will replace a prior immunobiology core that has served the ETMAD program well, but is no longer needed.
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