Generation, Metabolism, and Biological Function of Acid
Presenilin (PS) supports the intramembranous cleavage of several substrates, including Notch I-IV and the ß-amyloid precursor protein (ßAPP). In the case of Notch, the PS-supported cleavage results in the production of the Notch intracellular domain (NICD), which is required for signal transduction and the regulation of target gene transcription. In recent work, Dr. Haas and his colleagues identified the corresponding fragment of ßAPP called the amyloid precursor protein intracellular domain (AICD) and found that it is generated by a molecular mechanism that is very similar to NCID. He is now investigating the molecular mechanisms of AICD generation and analyzing the putative similarities of AICD and NICD generation as well as the influence of familial Alzheimer's disease-related mutations on the production of these two cytoplasmic fragments. It is hoped that the expression of the recombinant fragment in tissue culture cells under conditions where its degradation is blocked will help identify genes that are involved. Based on the phenotype obtained from Caenorhabditis elegans (a worm) and zebrafish, conclusions regarding the target genes can be made and genetic modifiers can be isolated. If successful, this project will not only help to identify a biological function of ßAPP but is also important for the development of therapies to block the generation of amyloid -peptide using gamma-secretase inhibitors.