The major focus of our work is on the amyloid precursor protein (APP) and the role it plays in the neuropathology of Alzheimer's Disease (AD). We also initiated a study on the regulation of the D2 dopamine receptor gene and its role in Parkinson's Disease, tardive dyskinesia and normal aging. We made three independent mutations within the APP gene (mAPPs) which are known to cause early-onset, familial AD or Hereditary Cerebral Hemorrhage with Amyloidoses-Dutch Type. Plasmids containing mAPPs were stably transfected into cell lines in order to examine phenotypic consequences to the cells and proteolytic processing of the expressed APPs. Neuronal and endothelial cells expressing mAPPs showed larger C-terminal fragments. NGF/cAMP treated PC-12 cells expressing mAPPs showed elevated levels of APP and C-terminal fragments. They had severely compacted cell bodies and eventually detached from the plates and died. We have cloned and characterized the 5' upstream regulatory region of the rat APP gene. A 375 bp fragment from this region functioned as a strong promoter in rat and human cell lines and its activity was enhanced by retinoic acid. The basal promoter activity was localized to a 75 bp sequence by deletional analysis. Finally, we isolated several DNA fragments from the functional promoter of the D2 dopamine receptor gene. Nuclear extracts from different tissues of young and old rats are being used with these promoter fragments to identify possible cis-acting transcriptional regulatory sites.
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