NEURAL HOMOLOG OF AMYLOID PROTEIN PRECURSOR

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The most striking feature of Alzheimer's disease is the accelerated appearance of amyloid in brain deposits. The beta amyloid peptide in these deposits is cleaved from a larger protein, beta amyloid protein precursor (APP). Current data suggest that APP displays an aberrant metabolic fate in brains afflicted with Alzheimer's condition. The APP gene encodes a family of proteins that shows ubiquitous distribution, however one form of APP, APP695 is nervous system-specific. A Drosophila gene Appl (Amyloid protein precursor-like) encodes a protein, APPL, that shows striking sequence homology to the nervous system-specific form of APP. Similarities of amino acid sequence, biogenesis, and spatial and temporal distribution have led to the hypothesis that APPL is a Drosophila homolog of neural-specific APP695, and furthermore that APP and APPL provide similar important functions within the nervous system. The proposed experiments are designed to test these suppositions and elucidate the in vivo role of APPL. These experiments will use molecular approaches and will take advantage of the genetic manipulations possible in Drosophila to create in vitro novel mutants in the Appl gene. In vitro mutated Appl genes will be introduced into the fly genome. The phenotype of Appl deletion mutants and the newly created novel mutants will be analyzed; the biogenesis of APPL and of mutant APPL forms will be studied in cell culture and in vivo; and biologically functional forms of the APPL protein and domains within the protein will be defined. Human-Fly chimeric genes will be tested in the in vivo functional assays. Genes that interact with Appl will be defined as a way to gain a thorough understanding of the biological processes that, APPL is engaged in. The proposed analysis can potentially contribute to the understanding of the function and metabolism of APP under normal conditions and in the degenerative disease state.