Neurotrophic factors are crucial for the survival and maintenance of neurons in the adult central nervous system (CNS). Nerve growth factor (NGF) is known to play an important part in survival and maintenance of cholinergic neurons of the basal forebrain (BF). Thus, pharmacological agents that enhance the expression of NGF may be proven to be effective in preventing neuronal degeneration. Little is known about mechanisms of regulation of NGF expression in the adult CNS. Moreover, it is yet unknown whether aging alters these mechanisms. This proposal will test the hypothesis that noradrenaline regulates the expression of NGF and other neurotrophins in the CNS of adult and aged rats. Data in support of this hypothesis have been obtained during the previous award period. In adult and aged rats, the activation of central beta-adrenergic receptors (BAR) increases NGF biosynthesis (mRNA and protein) in the cerebral cortex only. The anatomical specificity of this induction was confirmed by the fact that the mRNA for basic fibroblast growth factor was induced in additional brain areas. In adult rats, the cortical levels of NGF mRNA are also increased noradrenergic agonists which do not activate BAR suggesting that the noradrenergic input to the cerebral cortex is crucial for the expression of the NGF gene. This proposal will test whether the proposed pharmacological treatments also increase the expression of brain derived neurotrophic factor and neurotrophin-3, two other members of the neurotrophin family. The molecular mechanisms underlying the anatomical specificity of NGF induction will be investigated using neuroanatomical correlates (in situ hybridization). These studies will be complemented by experiments designed to test whether the proposed pharmacological manipulations activate the transcription factor AP-1 in the cerebral cortex of adult and aged rats. At the same time, correlative studies will be performed in adult and aged rats to establish whether the pharmacologically-induced NGF exerts biological activity by determining the activation of the high affinity NGF receptor trkA, and by assessing cholinergic function measured by choline acetyltransferase activity and choline uptake. Results from these studies will provide i) new insights into the mechanisms that regulate the expression of growth factors in the CNS and ii) a pharmacological basis for the development of a new therapeutic approach to neurodegenerative diseases.
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