Neurons degenerate and die as a result or cause of Alzheimer's Disease. Neurotrophic factors (NT) are molecules that can support the survival of neurons and their exogenous delivery to the aged brain may prevent, retard, or reverse neuronal degeneration. However, since the NTs are large molecules that do not easily pass the blood-brain barrier, they must be delivered directly to the brain. Intraventricular infusion results in the dilution of the NT in the intraventricular fluid; this method of delivery has the disadvantage of delivering the NT throughout the brain to areas that may not need the NT. Furthermore, the infusion method requires an indwelling cannula and an externally attached pump as a reservoir, an arrangement which is susceptible to infection. We have developed a method to implant autologous cells, genetically engineered to make and secrete NTs, directly into the area of the brain that can benefit from NT augmentation. We plan to further develop this strategy using nerve growth factor (NGF) as the NT and cholinergic neurons as the target neurons, as these are the neurons that degenerate with aging. We will study the long- term survival of primary fibroblasts genetically engineered to make and secrete NGF and their effect on cholinergic neuron survival and other morphological parameters. In addition, we will evaluate the effects of this therapeutic approach on cognitive behavior in aged, cognitively impaired rats. We are also studying other NTs, including BDNF, NT-3 and bFGF. In the future, we will expand on the basic strategy of gene delivery, using these trophic factors separately or in combination. These studies will provide an understanding of the role that these trophic factors play in neuronal and cognitive decline with age and will contribute to the continued development of the gene transfer/intracerebral grafting technique as an approach to the treatment of cognitive dysfunction.
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