Chapter 20 - Neurotrophic Factors, Gene Therapy, and Alzheimer's Disease

Abstract

Nerve growth factor (NGF) protection of cholinergic basal forebrain (CBF) neurons is of particular interest in the context of Alzheimer's disease (AD). A number of neuronal populations degenerate in AD, including cholinergic, noradrenergic, serotonergic, and several peptidergic neurons. The loss of CBF neurons is particularly severe, often affecting 75 to 80% of this population. The loss of CBF neurons has been correlated with the severity of synapse loss in the cortex, the density of amyloid plaques, the severity of clinical dementia, and the duration of disease. Because NGF protein levels in AD are increased in the neocortex but decreased in the CBF, diminished NGF receptor expression might be causally related to reductions in NGF transport in AD. This is particularly important because NGF is retrogradely transported to CBF consumer neurons after binding to receptors on cholinergic terminals in the neocortex and hippocampus. The lesions of the basal forebrain reduce NGF uptake and retrograde transport from cholinergic terminals within the neocortex and hippocampus in rodent models, resulting in elevated NGF levels in these regions. This chapter presents several gene therapy strategies applied to the correlative animal models of AD. In these models, NGF gene therapy has rescued cholinergic neurons and, in some cases, improved cognition.