These studies are based on our recent discovery of sprouting in the dentate gyrus of the AD brain and on the observation by our group and others that he AD brain expresses several developmental molecules reflective of growth- related events and plasticity mechanisms. Our data and those of others suggest that an accumulation of these compensatory mechanisms, along with a degenerative mechanisms, contribute to pathology, particularly senile plaque formation. Over the previous grant period we have characterized the responses of the dentate gyrus to entorhinal lesions in the rodent brain and compared these responses to the AD brain in which entorhinal cell loss also occurs but in which unusual pathologies emerge, such as senile plaques. The hippocampal/entorhinal complex appears well suited to extend studies to the regulation of protease inhibitors and the response of growth factor. Specifically, experiments will be carried out to examine the anatomical distribution of PN-1 and its regulation after lesions and trauma in the hippocampus. We will compare the response in the rodent brain to that in the AD brain, correlate this with more classic measures of AD and determine the specificity of the decrease to AD. We will perform the anatomical studies, and Dr. Dennis Cunningham and coworkers will carry out the biochemical measures. parallel experiments will be carried out with PN-2 in collaboration with Dr. Bill van Nostrand. Overall, as we learn about particular substrates and molecular systems, our goal is to relate these basic data to a well-characterized normal system. Previously, as part of this program, we demonstrated that injury causes a change in neurotrophic factor availability, apparently as a regulatory event in arresting second neuronal death and promoting sprouting. It is suggested that the cellular cascade associated with growth (microglia, astrocytes, and neuronal growth) gives rise to a growth factor cascade that sets the stage for repair, initiates growth, and determine the final outcome. Specifically, experiments are proposed to study the regulation of NGF levels in vitro in purified dentate gyrus neuronal cultures and examine the regulation by other growth factors, depolarization, and various receptor activators. We will carry out parallel in vivo experiments specifically initiated at determining whether FGF infusion regulates NGF mRNA. These experiments will be in collaboration will Drs. Gall and Isackson. We will extend our in vitro/in vivo approaches to FGF regulation as probes and antibodies become available.
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