This proposal will test the hypothesis that nerve growth factor (NGF) is a neurotrophic factor for cholinergic neurons of the forebrain. In an attempt to characterize the actions of NGF on these cells, the P.I. has found that NGF promotes survival of cholinergic septo-hippocampal neurons of adult rats after destruction of their processes by transection of the fimbria. Furthermore, preliminary findings indicate that NGF stimulates survival and fiber growth of cholinergic neurons in culture. Planned experiments aim at thoroughly investigating these previously undiscovered effects of NGF and at characterizing the conditions necessary for them to occur. Studies will be carried out in vivo, on young and aged adult rats with lesions of the septo- hippocampal cholinergic pathway, and in vitro, on cultured cholinergic neurons from fetal rat brains. In addition, an immunohistochemical method has recently been developed by the P.I. for the visualization of NGF receptors in the rat brain. Findings obtained so far, and which were limited to telen- and diencephalon, indicate that NGF receptors are selectively located on forebrain cholinergic neurons. Planned experiments aim at substantiating this selective localization of NGF receptors and at differentiating between a localization in cholinergic cells and afferent terminals. Furthermore, it is proposed to map NGF receptors in the entire rat brain. The proposed studies will help to establish whether NGF is a neurotrophic factor for forebrain cholinergic neurons. Furthermore, the studies have implications for Alzheimer's disease which is associated with a selective loss of cholinergic neurons in the basal forebrain. The proposed studies concern survival and function of a neuronal population selectively affected in Alzheimer's disease and the effects of a neurotrophic factor for these neurons.
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