The major objective of this proposal is to develop an understanding of actions of nerve growth factor (NGF) on neuronal gene control relevant to treatment of Alzheimer's disease (AD), a fatal neurodegenerative disorder of unknown etiology. Evidence suggests that NGF-responsive forebrain neurons involved in memory pathways are effected early in AD and may contribute to the dementia, leading to suggestion of NGF as a potential therapy. The basis of the pervasive changes in gene expression, protein processing and decreased oxidative metabolism in AD is unknown. To elucidate the mechanisms of NGF action towards the understanding and potential treatment of AD, we will use neurons in vitro to: (1) define NGF effects on regulation of specific genes, including the amyloid precursor gene; (2) examine molecular mechanisms of NGF action; (3) define effects of NGF on control of mitochondrial numbers in neurons; and (4) define effects of mitochondrial dysfunction in neurons on induction of stress genes and explore actions of NGF and acetylcarnitine in altering stress responses. In order to use neurotrophic factors including NGF in the treatment of AD, it will be necessary to predict actions in neurons. In neurons, study of mechanisms of gene control requires new approaches. Preliminary results demonstrate the feasibility of studying NGF-regulated gene expression in neurons in culture. In addition preliminary studies demonstrate the feasibility of introducing foreign genes using herpes simplex virus (HSV)- derived recombinant viruses and virus vectors. The methods proposed in this study should allow the study of gene regulation in neurons from embryonic animals or aged rats and allow development of model systems for the testing of potential therapeutic strategies for AD. Our hypothesis is that understanding gene regulation in neurons will have broad application to recombinants will provide a basis for developing agents for gene therapy in neurons with potential future uses in the central nervous system.
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