of work: A major focus of this project is to discover the roles of Amyloid Precursor Protein (APP) and Presenilins (PS) in the etiology and pathology of Alzheimer's Disease (AD). These proteins are important to study since the processing of APP and the effect of PS on APP processing bear directly on the increased production and deposition of Ab in senile plaques of AD. Brains of AD patients exhibit selective and massive neuronal loss. In light of recent evidence from our laboratory and others showing that, in cell culture, over-expression of mutated forms of APP and PS causes cell death, we were interested in examining the mechanisms involved in this cell death. One of the aims of our laboratory is to discover how APP or PS mutations lead to specific neuronal cell loss in AD. Previously we showed that over-expression of mutated forms of APP in stably transfected PC12 cells led to the increased production of intracellular, amyloidogenic C-terminal fragments of APP. This was accompanied by increased cell death over several days; this death appeared to be apoptotic by several criteria. Recently, we showed that transient expression of mutated forms of PS-2 also increased the amount of apoptosis in growth factor-dependent PC12 cells. In this same model system, the over-expression of an antisense PS-2 construct reduced the amount of apoptosis induced by mutant APPs suggesting that the two proteins may share the same pathway of cell death. Interestingly we and others showed that pertussis toxin treatment of cell lines over-expressing either mutated APPs or PS-2 prevents the apoptosis, suggesting that a G-protein-coupled signal transduction pathway may be involved. These results suggest that in AD, the selective neuronal cell loss may be, in part, due to an apoptotic mechanism. This provides a rationale for targeting particular elements of apoptotic pathways for therapeutic intervention in AD.
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