Atrophy of basal forebrain cholinergic neurons and decreased target acetylcholine levels are associated with impaired memory and cognitive function during aging and in Alzheimer's Disease. NGF significantly increases the cholinergic neuron size and acetylcholine synthetic enzyme ChAT activity and improves age-and lesion-related memory impairment. TrkA mediates NGF response by activation of the receptor-linked tyrosine kinase pathway while the p75 neurotrophin receptor can either facilitate TrkA response to NGF or induce cell death. We discovered that absence of p75 in transgenic mice results in an up-regulation of cholinergic neuronal features, including increased ChAT activity and target innervation, and hypertrophy of both TrkA-positive and-negative neurons. These data suggest a novel role for p75 in negatively regulating neurotrophic features. The objective of this proposal is to delineate mechanisms mediating these p75- negative effects and thereby identify specific and critical mechanisms relevant to declined cholinergic neuronal function in aging and Alzheimer's Disease. Hypothesis: p75 negatively regulates cholinergic neurotrophic features either through suppression of NGF/TrkA-mediated response or via direct activation of a TrkA-independent negative regulatory pathway. p75 regulates trophic features via different mechanisms depending of where TrkA is present and the developmental stage.
Specific Aim 1 : Determine whether the absence of p75 causes increased basal level and NGF-mediated cholinergic neurotrophic features in vitro. Basal level and effects of NGF on ChAT activity and cholinergic neuron size will be measured in basal forebrain septal cholinergic neuronal cultures derived from p75 +/+ and -/- mice.
Specific Aim 2 : Determine the signaling pathway mediating the p75-effects observed in Aim 1. p75 +/+ and -/- cholinergic cultures will be treated wit NGF inhibitors of either the TrkA-pathway of p75-pathway and cholinergic neuron size will be measured.
Specific Aim 3 : Determine whether p75 differentially regulates developmental hypertrophy versus age-related atrophy of cholinergic neurons in vivo. ChAT activity and cholinergic neuron size will be measured.
Specific Aim 4 : Determine during different developmental stages whether p75 differentially regulates the response of TrkA-positive and-negative cholinergic neurons to NGF. NGF will be infused into neonate, adult, and aged p75 +/+ and -/- ,ice. ChAT activity and cholinergic neuron size will be measured.
