CNS aging and neurodegenerative pathologies such as Alzheimer's disease are characterized by neuronal loss induced by a number of factors including decreased trophic factor signaling. The neurotrophins, NGF, BDNF, and NT-3 sustain survival of those neurons that are often affected by binding to specific tyrosine kinase receptors (trk), as well as to a common low affinity receptor (p75) whose function is not clear. NTs have been proposed as the basis for treatments to prevent neurodegeneration. A successful development of NT treatment requires a thorough characterization of the signal elements that transduce NT trophic action. This project focuses on the NGF-associated signal pathways involved in NGF mediated rescue from apoptosis. It is proposed that the stimulation of PKC-zeta and the activation of NF-kappa B are signal elements common to the activation of both NGF receptors. Using immortalized nigral and cerebellar cultured neurons transfected with either or both NGF receptors, Aim 1 will test whether binding to either Trk A or p75 may be sufficient to rescue cells from serum starved apoptosis.
Aim 2 will test whether there are signal molecules associated with p75 that can affect apoptosis.
Aim 3 will test whether PKC zeta activation or NF-kappa B translocation are signals common to both trk A and p75 receptors that are essential for rescue from apoptosis.
Aim 5 will test whether the apoptosis which occurs in the aged rodent is associated with altered PKC or NF-kB signaling and confirm the in vitro observations. These experiments will elucidate mechanisms that mediate NT support of neurons and provide useful information as to the development of therapies to counteract age and pathology associated neuronal apoptosis.
