Aging is associated with a loss of brain neurotransmitter function which apparently is the substrate for a diverse constellation of age-associated symptoms. Systemic administration of GM1 ganglioside, a normal constituent of the membranes of the brain, enhances cholinergic neurochemical and morphological markers in the brain of aged (22-24 month old) rats. We now provide evidence that GM1, also, improves the neurochemistry and morphology of dopaminergic neurons in the aged brain. The improvement of cholinergic and dopaminergic neuronal activity is accompanied by enhanced cognitive and motor performance. GM 1-induced recovery of function in aged animals is long-lasting, as both neurochemical and behavioral enhancement is maintained for 15 days after the discontinuation of GM1 treatment. In many aspects, the trophic actions of the GM1 in various systems resemble those of the neurotrophins. Based on these observations, we speculated that GM1 might exert its trophic effects, in part, by interacting with the neurotrophins. Recently, this notion has been supported by observations that NGF and GM1 display pharmacological synergism, and that in cell lines GM1 induces tyrosine phosphorylation of the NGF receptor TrkA. We provide evidence that GM1 is capable of inducing Trk tyrosine phosphorylation in brain tissues in situ and in vivo. Interestingly, GM1 tyrosine phosphorylation of Trk is maintained in aged animals. Our general goals are: (1) to continue exploring the consequences of administering GM1 on brain neuronal neurochemistry, morphology and behavior in aged animals; and (2) to investigate the molecular mechanism(s) of the GM1 neurotrophic action. In this regard, dopaminergic and serotonergic neurons of aged brain will be studied, as they are important contributors for the pathogenesis of age-associated motor, cognitive and mental disorders. The interaction of GM1 with other neurotrophins, BDNF and NT-3, will be investigated, and, the role of GM1 for Trk neurotrophin receptor tyrosine phosphorylation and signaling pathways will be explored. Understanding the mechanism(s) underlying the neurotrophic actions of GM1 in vivo will validate the utility of the ganglioside as a putative therapeutic modality for treating/preventing age-associated symptomatology. GM1 has major therapeutic advantages over the peptide neurotrophic factors; it can be administered systemically and its action is long-lasting. More importantly, GM1 can serve as a model molecule for the synthesis of neurotrophic drugs with better bioavailability and efficacy, and with limited side effects.
