Role of Trophic Factors in Neuronal Aging

Abstract

Neuronal cell death is an event associated with the pathophysiology of nerve injury, stroke and aging that is also a positive regulatory element in neuronal development. Whereas in all the aforementioned, the neurite outgrowth, as a part of the spectrum of responses by the surviving neurons, has been extensively studied at the molecular level; less is known about the molecular mechanisms that determine cell survival, except for the many classical biological experiments that have established that in vertebrate development, neuronal cell death is, in large measure but not uniquely, under the control of neuronotrophic factors such as the nerve growth factor protein, NGF (Thoenen et al., 1981). Two hypotheses have been proposed to explain the phenomena resulting in neuronal death. One hypothesis is that neurons are particularly susceptible to free radical damage because of their very low basal endogenous levels of antioxidants and antioxidant enzymes and that neuronotrophic factors acting through their respective cell surface receptors can shift the oxidant-antioxidant balance through induction of antioxidant enzymes (Perez-Polo et al., 1986). The second hypothesis proposes that there are “suicide genes” whose repression by NGF results in cell survival (Martin et al., 1988). Following axotomy to peripheral sympathetic and sensory neurons or the more central projections of the basal forebrain into the hippocampal areas, NGF has also been shown to be necessary to peripheral regeneration and to sparing effects on cholinergic basal forebrain neurons following deafferentation. NGF has dramatic trophic effects on cholinergic neurons of the CNS in vitro, a regeneration paradigm (Bostwick et al, 1987; Hatanaka et al, 1988). In aged rodent and human CNS and PNS, there are reported decreases in the levels of NGF and its receptor, NGFR (Goedert et al, 1986; Angelucci et al, 1988; Uchida and Tonionaga, 1987). In the periphery, NGF has well documented effects on certain neuronal and non-neuronal cells alike whose physiological relevance is not understood in a definitive fashion (Levi-Montalcini, 1987; Lillien and Claude, 1985; Thorpe, et al., 1988).