Control of Neuronal Differentiation: Role of Adaptor Proteins

Alzheimer’s disease is a disorder which is characterized by a progressive impairment in intellect and memory. Pathological studies of brains affected by Alzheimer’s disease demonstrate a degeneration and eventual loss of numerous types of neurons, including those termed cholinergic neurons. These cells are of particular clinical importance, as their degeneration leads to a decline in memory.

These cholinergic neurons bear on their cell surface specific receptors for factors which mediate their survival and development. One protein factor, termed nerve growth factor (NGF) acts on these cells by binding to receptors, and then transmitting specific signals to the interior of the cells which promote cell survival. This observation has prompted animal studies of NGF, infused into the fluid surrounding the brain, to determine if NGF could influence cholinergic neuron function. In these studies, continuous administration of NGF prevented neuronal atrophy, and augmented expression of neurotransmitters important in memory. These findings supported the hypothesis that NGF could be used in patients with Alzheimer’s disease to improve cognitive function. However, administration of the drug would require delivering NGF to the fluid surrounding the brain, necessitating the use of indwelling catheters. One approach to modulating the effects of NGF on these neurons, without infusing NGF into brain fluid, is to define the specific intracellular mediators which allow NGF to enhance neuronal survival and function. Once these intracellular proteins have been defined, then drugs could be developed to enhance their function and promote their actions.

The initial interaction of NGF with receptors on the surface of neurons leads to a cascade of intracellular events, culminating in the promotion of cell survival. Many of the initial intracellular events are very similar to those seen after the stimulation of cells to replicate and divide. If drugs are to be developed which mimic the action of NGF, they will need to be directed towards intracellular pathways which promote cell function and survival, not which induce cell proliferation. Therefore, in this proposal we seek to define the mediators of NGF action which are specific for enhancing neuronal function.