Our long-term objective is to gain insight into the cellular and molecular mechanisms underlying the initiation and progression of neuronal death in the brain, particularly in brains of Alzheimer patients. The goal of this pilot study is to establish a culture study of fetal brain cells derived from """"""""normal"""""""" human abortuses and from Down Syndrome (DS). These cultures will serve as models for the study of processes leading to neuronal death in Alzheimer disease. The rational for choosing the DS brain is based on the consistent findings that DS patients develop Alzheimer neuropathology at a much earlier age than """"""""normal"""""""" aging people and on the hypothesis that processes leading to Alzheimer neuropathology at a much earlier age than """"""""normal"""""""" aging people and on the hypothesis that processes leading to Alzheimer neuropathology are operative at an earlier age, possibly already even in the fetus. S.A.1. Establish a human model system for the study of the regulation of neuronal survival Aggregate cultures comprised of neurons and glial cells will be established from dissociated brain cells obtained from the cortex of """"""""normal"""""""" human abortuses and of DS brains, using our previous experience with this culture system derived from rat fetal brains as a guideline. Two population of peptidergic neurons, neuropeptide Y (NPY) and somatostain (SRIF), will serve as model neurons. The morphological and functional differentiation of these neurons and the topographical arrangement of the cells will be defined. S.A.2. Test our """"""""ping pong"""""""" hypothesis of basic fibroblast growth factor (bFGF) - Beta-amyloid interactions. Neurite sprouting has been implicated in the early stages of senile plaque formation in Alzheimer disease. Our working """"""""ping pong"""""""" hypothesis is that bFGF stimulates expression of the gene encoding Beta-amyloid precursor protein (APP), a product(s) of which, in turn, stimulates more bFGF production. Thus, each round of bFGF - Beta-amyloid interaction results in greater extracellular levels of agents capable of promoting neurite sprouting, of which Beta-amyloid may be a substantial component. We will initiate this study by assessing the effect of bFGF on neurite sprouting and survival of NPY/SRIF neurons in our human model systems. These results will serve as the basis for a full-scale research proposal to elucidate the cellular and intracellular mechanisms underlying bFGF - Beta-amyloid interactions in processes leading to neuronal death.
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