Alzheimer's disease is an insidious neurological disease which causes severe dementia. It is marked by a number of specific pathological changes in the brain, including a loss of brain stem cholinergic and noradrenergic neurons, and the appearance of neurofibrillary tangles and senile plaques. The cause of Alzheimer's disease and the origin of these pathological changes are unknown. One hypothesis suggests that Alzheimer's disease and its symptoms are caused by a deficit of neurotrophic hormones in the brain. One such neurotrophic hormone, which has recently been found in rat and rabbit brain, is nerve growth factor (NGF). NGF has long been known as an important hormone in the peripheral nervous system, where it is required for the growth, development, and maintenance of certain sensory and sympathetic nerves. Although its role in the central nervous system has not been as well studied, it is clear that in the rat, NGF is synthesized in the cortex, hippocampus, and olfactory bulb, and that NGF, when injected into the brain, is transported by cholinergic neurons to cell bodies in the nucleus basalis and septum. NGF may also regulate brain acetylcholine levels. The NGF system consists of the three subunits of the 7S NGF complex, the enzymes that process the beta-NGF precursor, and the receptor that binds and transports NGF to the cell bodies. A defect in any one of these components could affect the synthesis or transport of NGF, robbing neurons of an essential factor. The goal of our research is to demonstrate the presence of mRNA coding for NGF, its receptor, and its processing and regulatory proteins (kallikreins) in postmortem human brain, and to determine whether the amounts of these mRNAs are altered in Alzheimer's disease. Using sensitive dot and Northern blotting techniques and a variety of nucleic acid probes, we will compare levels of NGF mRNA in normal and Alzheimer's disease brain tissue. We will determine whether human brain synthesizes alpha- or gamma-NGF subunits. We will also compare mRNA levels for NGF receptor and specific kallikreins (including alpha and gamma subunits, if indicated). Depending on the results, we will proceed with experiments designed to study whether Alzheimer's disease could be caused by a genetic defect in NGF or associated genes, a defect in RNA synthesis or processing, a receptor defect, or a problem in retrograde transport. We will also determine whether there are age-related changes in NGF, NGF receptor or kallikrein mRNA content, in normal and Alzheimer's disease brain tissue.
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