DESCRIPTION (From the applicant's abstract): The neuronal production of amyloid beta (beta) from the amyloid precursor protein (APP) appears to be a necessary and invarieant step in the progression of Alzheimer's disease (AD). Three genes have been linked to early-onset AD. These genes are presenilin 1 (PS1), presenilin 2 (PS2), and APP itself. Mutations in each of these genes lead to the elevated proteolytic processing of APP into Abeta species that aggregate more readily and form amyloid plaques. The fact that three separate genes implicate Abeta as the causative agent of Alzheimer's disease makes this an important target for theraputic intervention. One way to create therapies for AD is to block the proteases that generate Abeta. These proteases have not been unidentified but the activities that create Abeta are termed beta and gamma secretase. The role of gamma secretase is especially important in the progression of AD since this activity can produce more or less aggregating forms of Abeta. It is the aim of this proposed study to characterize the role of PS1 in gamma secretase activity, identifying the subcellular localization of gamma secretase activity, and lastly to identity the gamma secretases. This will be accomplished through biochemical manipulation of cell extracts and monitoring gamma secretase activity in an in vitro assay. The identification of the protease(s) involved in producing abeta at the gamma secretase site will drastically further knowledge of the molecular mechanisms underlying AD and improve chances of creating theraputic inhibitors that slow or stop the progression of AD.