p75mediated Death of BF Cholinergic Neurons by proNGF

Basal forebrain cholinergic neurons (BFCN) are particularly vulnerable to degeneration in Alzheimer’s disease, so there is significant interest in understanding the role of factors influencing the survival and death of these neurons. The neurotrophins are a family of factors, including nerve growth factor (NGF), which have been studied extensively for their ability to support the survival of BFCNs. Most of the trophic actions of these factors, (those influencing cell survival, differentiation, neurotransmitter synthesis etc.) require the activation of a family of receptors knows as Trks. Neurotrophins are synthesized as larger precursor molecules which are cleaved to form the mature trophic factor. They can bind to an additional receptor known as p75, which has been shown to induce cell death in certain situations. Recent studies have now demonstrated that the pro-neurotrophins, in particular proNGF, can selectively bind to p75 with high affinity without binding to the Trk receptor, and can induce cell death. ProNGF has been detected in both rodent and human brains, and is elevated in AD. Understanding the signals that cause neurons to die may be critical to understanding the underlying pathology of AD. The goal of this study is to determine whether proNGF has the capacity to elicit cell death in this critical neuronal population, and will begin to elucidate some of the important cell death signaling characteristics of this pathway.