Nerve Growth Factor and Its Receptors in the Primate Forebrain

Abstract

The selective vulnerability of specific neuronal populations in the brain is a feature of various neurological disorders, including Alzheimer’ s disease (AD). A consistent and early pathological feature of AD is the degeneration of cholinergic neurons in the basal forebrain (Bartus, 1982; Whitehouse et al., 1983; Mufson et al., 1989). Cortical cholinergic deficits resulting from atrophy and degeneration of basal forebrain neurons correlate better than any other neurochemical change with the memory impairment seen in patients with AD (Bierer et al., 1995). It is now well documented that neurotrophic molecules play a pivotal role in the survival and maintenance of some adult neurons, including those of the cholinergic basal forebrain (CBF) (see Hefti et al., 1989, for review). Nerve growth factor (NGF) is the prototype neurotrophic molecule, which was first characterized by Levi-Montalcini and coworkers as a protein supporting the survival and phenotypic differentiation of catecholamine-containing peripheral sympathetic ganglia (see LeviMontalcini and Angelleti, 1968; Thoenen and Barde, 1980). It is now well established that NGF is one member of a superfamily of neurotrophic substances that includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), neurotrophin-5 (NT-5), and NT-6 (Maisonpierre et al., 1990; Bothwell, 1991; Ibanez et al., 1992; Ip et al., 1992; Jing et al., 1992; Barbacid, 1994; Koster et al., 1994). Six regions of amino-acid nonidentity confer specificity for each neurotrophin (Ip et al., 1993). Initially, a potential role for NGF as a trophic molecule for the CBF neurons was inferred from the seminal retrograde transport studies of Schwaab et al. (1979) and Seiler and Schwaab (1984). In these studies, retrogradely labeled neurons were observed within the septal—diagonal band complex or the nucleus basalis magnocellularis following injection of iodinated NGF into cortex and hippocampus, respectively. Autoradiographic investigations revealed that neurons that bind radiolabeled NGF codistribute with CBF neurons (Richardson et al., 1986). Converging lines of evidence then indicated that NGF modulates the development, survival, and maintenance of CBF neurons (Hefti et al., 1989). NGF is found in highest concentrations within target sites of CBF perikarya, such as the cerebral cortex, hippocampus, and olfactory bulb (Whittemore and Seiger, 1987). NGF increases choline acetyltransferase (ChAT) levels in cultured septal and striatal cholinergic perikarya (Hefti et al., 1985; Martinez et al., 1985). Intraventricular injections of NGF in neonatal rats increases ChAT activity in the basal forebrain, hippocampus, cortex, and striatum (Gnahn et al., 1983; Mobley et al., 1985). Evidence also has been accumulating that NGF may modulate regenerative events within the CBF. For example, infusion of NGF, transplantation of NGF-containing mouse salivary gland, and grafting of capsules containing cells modified to secrete NGF rescue medial septal cholinergic neurons that undergo degeneration after transection of the fimbria—fornix system (e.g., Hefti et al., 1986; Williams et al., 1986; Springer et al., 1987; Emerich et al., 1994; Kordower et al., 1994c). Indeed, some of these approaches attenuate cognitive deficits resulting from septohippocampal axotomy (Will and Hefti, 1985; Springer et al., 1987). Aged rats exhibit cognitive impairments, degeneration of the CBF neurons, and changes in NGF, similar to that seen in animals with experimental lesions of this system (see reviews in Collier and Coleman, 1991; Scott and Crutcher, 1994; Scott et al., 1994). For example, aged rats with memory impairment, but not aged rats without memory impairment, show exaggerated neuron loss and atrophy of CBF neurons and decreased levels of cortical cholinergic markers (Biegon et al., 1986; Fischer et al., 1987; Koh and Loy, 1988; Koh et al., 1989; Markram and Segal, 1990). Recently, Cooper and coworkers (1994) demonstrated that retrograde transport of iodinated NGF from hippocampus declines in aged rats (no behavioral characterization). This study also revealed that CBF neurons in the aged rat exhibit diminished levels of the message for the high affinity Trk A receptor, but retain normal levels of the low affinity neurotrophin receptor (NTR) p75 mRNA. These observations suggest a relationship among age-related changes in retrograde transport of NGF, the expression of its signal-transducing high-affinity receptor, and morphological changes within CBF neurons.