The familial Alzheimer's disease gene product amyloid Beta (ABeta) precursor protein (APP) is processed to generate ABeta which is considered to be one of the major culprits of Alzheimer's disease. APP is first processed extracellularly by the alpha- or Beta-secretase creating either a C83 or C99 membrane tether fragment, respectively, and then by the gamma-secretase in the transmembrane domain. Processing by the Beta- and gamma-secretase leads to production of ABeta as well as AID (APP Intracellular Domain) which is derived from APP's extreme carboxy terminus. AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression and cellular calcium homeostasis. APP is a member of a gene family that includes the APP like molecules APLP1 and APLP2. Studies using knock out mice have demonstrated that APP, APLP1 and APLP2 have partially redundant functions as well as unique roles. Since APP signals by releasing the biologically active AID peptide, it is possible that APLP1 and APLP2 also release biologically active APP Like Intracellular Domains ALIDs due to processing by the g-secretase. The major goals of the current proposal are to characterize the signaling pathways regulated by APP, APLP1 and APLP2 processing. These studies could unveil the signaling pathways that are either common or specific and unique to each APP family member. In this context, we will also study the trafficking of APP family members in primary neurons. The transport of APP in neurons may be of great relevance to the biological function of APP in neuronal ceils and may regulate neurite growth. These studies may clarify the biological role of APP family members and have important practical applications in the development of new compounds for the cure and or prevention of Alzheimer's disease.
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