NEUROTROPHIC SUPPORT IN AGING AND ALZHEIMER'S DISEASE

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Age related loss of cognitive ability, most severely experienced in Alzheimer's disease, affects an increasing number of the elderly. Degeneration and death of neurons in the cerebral cortex, hippocampus and basal forebrain are the main events causing such loss of cognitive abilities. If therapies to attenuate such degenerative events are to be developed, it is of central importance to understand the molecular and cellular mechanisms that are involved in the maintenance, neuronal plasticity and regeneration of the central nervous system. Growth factors and their receptors represent one of the main molecular mechanisms promoting neuronal survival and regeneration. This project will investigate the role of fibroblast growth factors (FGF) in the aging and degenerating CNS. The focus of the project will be on acidic FGF (aFGF), basic FGF (bFGF), FGF-5 and their receptors. These factors are of specific interests in that they can promote neuronal survival as well as mitogenic responses of non-neuronal cells to injury; in addition they are present in specific cellular populations within cerebral cortex, hippocampus and basal forebrain. It is the goal of the present study to determine how the function of the FGFs is affected in aging and Alzheimer's disease. The specific aims of the study are: 1.To determine the levels and cellular distributions of specific FGFs and FGF receptors in normal adult hippocampus, cerebral cortex and basal forebrain. 2.To determine changes in levels and cellular distribution of specific FGFs and FGFRs in normal aging, in an animal model of age related hippocampal dysfunction, and in Alzheimer's disease. 3.To characterize mechanisms that may cause age related changes in the expression of FGFs and FGFRs. 4.To characterize the physiological role of FGFs in hippocampus, cortex and forebrain. 5.To test whether exogenous application of FGFs can ameliorate the deficiencies observed in an animal model of age related hippocampal dysfunction. The study will use a combination of biochemical, immunochemical, and molecular techniques to determine the levels, distribution and changes in expression of FGFs and FGF receptors. The study will focus on investigating the role of these molecules in Alzheimer's disease and in an animal model of-age related cognitive dysfunction.