Processing of Mutant Amyloid Precursor Proteins

         Alzheimer’s disease (AD), a devastating neurological disease, affects over 10% of the population over the age of 65 years. One of the distinctive features of its neuropathology is the formation of amyloid plaques in the brain. The B/A4 protein is a major component of amyloid. This protein is made from a larger precursor, the amyloid precursor protein (APP).         Six disease related APP mutations have recently been described. One of these is associated with a related amyloid associated disease, HCHWA-D, four others are associated with AD and one appears to be associated with individuals who show symptoms of both diseases. Little is known about why these altered precursor proteins result: in the formation of amyloid deposits.          We have expressed two of these mutations in the model baculovirus expression system. We find that these mutations cause alterations in secretion and processing of the APPs. Based on our findings we hypothesize that the mutations increase the secretion of an alternatively processed APP that can cause amyloid deposition.         We plan to further our findings by expression and analysis of all six mutations. In addition, we plan to explore the mechanism of amyloid formation using a cell-free model system. Further, we will verify results obtained in these model systems by analysis of fibroblasts and lymphoblasts from affected/ unaffected members of families that possess the mutations and from normal individuals. This knowledge will ultimately result in newer strategies for prevention of amyloid deposits and hence AD.