The functional state of the aged and Alzheimer's disease (AD) brain is most likely a dynamic equilibrium between the consequences of neurodegenerative events and the plastic mechanisms that attempt to compensate. The core proposal concentrates on this theme and involves a detailed analysis of entorhinal hippocampal circuitry in relation to plastic and pathological events. In AD the netorhinal cortex and hippocampus are particularly susceptible to pathology but also capable of plasticity. In animal models there is now extensive data on the mechanism of neuronal degeneration, plastic responses to neuronal loss and on hippocampal function in relation to cognition. A multidisciplinary approach is proposed that is designed to stimulate new discoveries in the etiology and treatment of AD. Three new projects and five pilot projects are proposed by the principal investigator and junior investigators in this group. Junior investigator projects: 1. Cellular and molecular mechanisms of plaque formation (J. Geddes). 2. Regulation of glial transport processes in aging and AD (R. Bridges). 3. Calcium homeostasis in peripheral cells from aged and AD patients (C. Peterson). Pilot projects: 1. Regulation on nerve growth factor mRNA in neurons and glia (P. Isackson). 2. Detoxification mechanisms in the aged and AD olfactory bulb (M. Leon). 3. Computer simulation of normal and abnormal synaptic transmission in Ad (D. Perkel). 4. MR imaging of limbic-hippocampal circuitry in AD (O. Naldoglu). 5. Motor memory compared to verbal memory in AD (M. Kean). Several themes run though the proposal. For example projects will focus on the hippocampal limbic system as related to olfactory function and cognition involving olfactory stimuli. At a molecular level we have emphasized neurotrophic functions, calcium homeostasis, and trophic mechanisms that may counteract, or even paradoxically, contribute to AD pathology. In this way research collaborations and new discoveries will be stimulated. Members of this program will also train pre- and post-doctoral students in aging and AD research. They will also participate in a seminar series which will catalyze new interactions and attract new investigators into the project.
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