Converging lines of evidence have suggested that cholinergic basal forebrain [CBF] neurons are sensitive to the trophic effects of a number of growth factors including nerve growth factor [NGF] and fibroblast growth factor [FGF]. Furthermore, these neurons require NGF for their survival and phenotypic differentiation. CBF neurons consistently degenerate in Alzheimer's disease (AD). These data, along with the substantial clinical and experimental literature implicating CBF systems in normal cognitive processes, has led to the hypothesis that administration of growth factors such as NGF may prevent the degeneration of CBF neurons in AD. One shortcoming of this contention is the paucity of supporting data gathered in nonhuman primates. This proposal aims to examine the structural and functional consequences of peripheral nerve grafts upon nonhuman primate CBF neurons. Following peripheral nerve transection, Schwann cells which ensheath peripheral nerves begin de novo synthesis of a number of growth factors and neurite promoting molecules including NGF, ciliary neuronotropic factor, brain derived neuronotrophic factor, laminin, and possibly FGF. We have previously demonstrated that peripheral nerve provides trophic and neurite promoting effects upon primate adrenal chromaffin cells following grafting into parkinsonian monkeys. Recently we have demonstrated that axotomized monkey CBF neurons can be rescued following peripheral nerve grafts if the implant precedes neuronal degeneration. Peripheral nerve grafts also invoke a cholinergic sprouting response. The proposed experiments intend to expand upon these latter observations. The long-term trophic and neurite promoting effects of peripheral nerve implants will be assessed and the dependence of these effects upon the continued presence of the graft will be determined. NGF levels produced by the implant will be quantified over time. Possible detrimental effects of peripheral nerve implantation will be determined via in situ hybridization for the beta amyloid precursor protein and with an immunocytochemical analysis of abnormally synthesized cytoskeletal proteins. The ability of aged primate transected nerve to manifest trophic influences upon NGF sensitive cells will also be determine. NGF production in severed peripheral nerves from young and aged monkeys will be compared in vitro and following grafting. The ability of autologous peripheral nerve grafts to prevent experimentally induced CBF neural degeneration in aged monkeys and the ability of such grafts to reverse age-related cognitive dysfunction will also be assessed. These studies will establish whether peripheral nerve grafts are a good donor source for reversing the consequences of basal forebrain degeneration in primates and will shed light on whether this approach is relevant for the treatment of AD.
