Neurotrophic Factor Therapy of Alzheimer’s Disease

Abstract

Dementia associated with high numbers of neuritic plaques and neurofibrillary tangles, detected post-mortem, are the defining features of Alzheimer’s disease. In addition, there is region-specific loss of neuronal populations. There is general cortical shrinkage as well as regional and cell-specific degeneration and loss of neurons. The temporal lobe seems to be more affected than other cortical areas. There is degeneration of neuronal populations providing ascending afferents to hippocampal and cortical structures. Such changes are most prominent in the cholinergic basalo-cortical and noradrenergic coeruleo-cortical systems. NGF has been proposed as therapeutic treatment for Alzheimer’s disease, based on the loss of cholinergic neurons and the pronounced trophic action of NGF on these cells. There is a decrease of cholinergic function in hippocampus and cortex illustrated by a loss of presynaptic cholinergic markers, ChAT activity, high-affinity choline uptake, the number of nicotinic receptors (Bowen et al., 1976; Davies and Maloney, 1976; Araujo et al., 1988) and a loss of cholinergic cell bodies in basal forebrain which provide the innervation of cortex and hippocampus (Whitehouse et al., 1982). These cells express rather selectively the NGF receptor proteins, gp145^{trk A} and p75^LNGFR. In animals, experimental lesions of the cholinergic neurons innervating hippocampus and cortex result in pronounced deficits in memory and cognitive functions which can be reversed by administration of drugs enhancing cholinergic function (Murray and Fibiger, 1985; Ridley et al., 1986; Tilson et al., 1988; Miyamoto et al., 1989). Enhancement of cholinergic function by drugs (e.g., acetylcholinesterase inhibitors) in Alzheimer patients produce modest, but significant ameliorations (Mohs et al., 1985; Thal et al., 1986; Eagger et al., 1991; Davis et al., 1992; Farlow et al., 1992).