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We have examined alterations in gene expression in neuronal cells exposed to toxic concentrations of AÃŸ using the Serial Analysis of Gene Expression (SAGE) technique. We have shown that AÃŸ impairs the degradation system of neurons, and leads to accumulation of a "memory suppressor" factor, ATF4, that hinders the ability of the PKA enzyme to transfer a phosphate molecule to the "memory enhancer" molecule, CREB1. Using drugs which specifically affect PKA activity, we were able to restore the ability of neurons to respond to "memory triggering" stimuli. These studies suggest that the earliest effects of AÃŸ are on memory formation itself and identify some molecules that can be candidate targets for new therapeutic treatments.
We have also used SAGE to better understand how neurotrophic factors such as Nerve Growth Factor (NGF) affect the nerve cell throughout its life cycle. Previously, a variety of approaches had been used to identify about 50 genes which responded to NGF. However, scientists have long estimated that a much higher number of genes, perhaps on the order of 1000, are affected by NGF. We have carried out SAGE profiling of messenger RNA transcripts derived from rat PC12 cells before and after exposure to NGF. matched 150 transcripts to named genes, the majority of which were not previously known to be NGF-responsive. Aside from confirming known NGF responsive genes, we have identified approximately 130 additional genes that appear to undergo significant levels of regulation by NGF.