Cholinergic neurodegeneration in Alzheimer's disease: Basis for nerve growth factor therapy

Abstract

Neurotrophins play an important role in the survival, differentiation, and maintenance of neurons selectively involved in a number of disorders of the nervous system. Nerve growth factor (NGF) plays a vital role for basal forebrain cholinergic neurons (BFCNs), including the maintenance of the cholinergic phenotype in adults. Recognition of this role has suggested the use of NGF to ameliorate the loss of these neurons in Alzheimer's disease (AD). While clinical studies directed at supplying NGF to patients continue to be pursued, fundamental questions remain as to the relationship between selective vulnerability of cholinergic neurons and the actions of NGF. In this chapter, we review the structure and function of the basal forebrain cholinergic system, its role in higher cognitive functions, and the importance of NGF actions on these cells. Studies that link changes in NGF signaling to the degeneration of BFCNs are then discussed, as are current approaches to NGF-related treatments. Finally, on the basis of recent findings in mouse models of AD and Down syndrome, we suggest that impaired retrograde axonal transport of NGF plays a significant role in pathogenesis. This insight may guide future studies of pathogenesis and innovative treatment for BFCNs and, perhaps, other neurons affected in AD.