Beta amyloid (betaA) is a product of amyloid precursor protein (APP) processing which is present in high concentration in the senile plaques of Alzheimer's disease (AD). There is some evidence that its neurotoxicity can be prevented by the application of specific neurotrophic. This proposal seeks to study the effects of a number of prospective growth factors and estrogen on the cholinergic neurons of the septal nucleus, a subpopulation of neurons which are at particular risk in AD. The hypothesis is that these growth factors may reduce neurodegeneration due to betaA. In this project a bilaminar culture system in which neurons and glial cells are cultured on separate planes, separated by about 1 mm will be used. This bilaminar system will allow us to grow cultured neurons in the absence of serum. This is necessary in order to assess the effects of individual growth factors and eliminates the confounding influences of the blood brain barrier and multiple cell types. In addition, this proposal seeks to study the effects of this toxic protein on cultured astrocyte glial cells, since, frequently, neurotoxicity is altered by glial cells, The specific questions to be asked are: 1) Do growth factors prevent beta A effects on septal cholinergic neuronal survival, differentiation (as measured by choline acetyltransferase expression), synapse formation (as measured by synaptophysin expression) or development (as measured by changes in neurite number, length, and branching characteristics)? 2) Does betaA alter glial cell survival, structure or differentiation (as measured by changes in vimentin, glial fibrillary acidic protein, or S100B expression? If there are such effects, might they be presented by the addition of exogenous growth factor? 3) Do growth factors alter the expression of betA or is aggregation? The specific growth factors to be studied would include: nerve growth factor, basic fibroblast growth factor, insulin-like growth factors I and II, and estrogen.
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