The etiology of Alzheimer's disease remains unknown. However, recent results strongly support the hypothesis that alterations in amyloid processing may underlie the chief neuropathological features of this disorder (senile plaques and neurofibrillary tangles). In addition, considerable evidence supports the conclusion that the basal forebrain cholinergic neurons are also affected in this disease and may contribute to the mnemonic symptomatology. One hypothesis is that alterations in basal forebrain neurons reflect a disruption of trophic relationships with their cortical and subcortical targets. In particular, the demonstration that Nerve Growth Factor (NGF) is present in the CNS, as well as its demonstrable pharmacological effects on basal forebrain cholinergic neurons in rodents and primates, have led to the hypothesis that reductions in NGF underlie the degeneration of basal forebrain neurons in Alzheimer's disease and that NGF might be useful therapeutically. furthermore, the classical demonstration of """"""""dystrophic"""""""" neurites in regions of senile plaques has been suggested to reflect abnormal (either increased or decreased) trophic activity in these areas. Recent results from this laboratory demonstrate an increase in NGF-like immunoreactivity in Alzheimer's cortex. In addition, tissue culture experiments carried out with sections of Alzheimer's brain tissue demonstrate that senile plaques alter neuronal form in culture and appear to inhibit neurite outgrowth. Building on these initial findings, the work outlined in this application will focus on two major hypotheses: 1) Alzheimer's disease is characterized by an increase in NGF due to degenerative changes in the basal forebrain and 2) Senile plaques exhibit inhibitory effects on neurite outgrowth in culture. These hypotheses will be tested experimentally by measuring NGF-like immunoreactivity with sensitive 2-site immunological and biological assays in several cortical and subcortical brain regions from Alzheimer's and control brains. In order to determine the effect that plaques have on neurite outgrowth, dissociated and explant cultures of chick sympathetic neurons will be established on tissue sections from Alzheimer's and control brains. The dynamic interactions of growth cones with senile plaques will be monitored using vital staining of living neurons in culture. The overall goal of the proposed work is to determine what role, if any, NGF may have in Alzheimer's disease and whether senile plaques represent sites of negative influence on living neurons. Answers to these questions will permit assessment of the rationale for using NGF therapeutically in this disease as well as address the current controversy over the role that senile plaques play in the etiology of Alzheimer's disease.
