Recent evidence indicates that the amyloid p protein precursor (APP) gene is a member of a highly conserved family of related genes. An APP-like gene (APPL) has been isolated from Drosophila and another has been reported in the form of a partial cDNA isolated from rat testes. More recently, our laboratory has isolated human cDNA clones encoding two novel APP-like proteins (amyloid precursor-like proteins, APLP1 and APLP2). These proteins are highly homologous to APP at the amino acid level. The beta-A4 domain is only partially conserved in APLP1 and APLP2, however, the remarkable degree of conservation of amino acid identity and specific domains within this protein family suggest that these proteins may share common functions, and, perhaps interact with common factors that are involved with protein processing and gene regulation. Based on our preliminary findings, we propose that production, maturation, and metabolism of APP, APLP1, and APLP2 in neurons in which these proteins appear to be co-expressed, may be critically balanced. We hypothesize that changes in the stoichiometry of APP, APLP1, and APLP2 message and/or protein effectively divert APP into alternative metabolic pathways including those predisposed toward amyloid formation. We have mapped the human APLP2 gene to chromosome 11, and the APLP1 gene to the proximal long arm of human chromosome 19 where a late-onset form of FAD has also been assigned making APLP an excellent candidate for this gene defect. We propose to further characterize APLP1 and APLP2 and isolate other members of the APP-like gene family, concurrently comparing gene expression, regulation, and processing of these proteins. We have chosen to explore the APLP family at the DNA, RNA and protein levels because we believe that the potential importance of these novel proteins in the etiology of Alzheimer's disease and aging deserves such a prompt overall assessment. We fully appreciate that comprehensive studies of expression, regulation and processing of the APLP family could each entail grant proposals of their own. Therefore, we have devised a set of experiments aimed at providing in a focused manner, critical data points in each of these areas of investigation. The ultimate goal of the experiments proposed is to provide a rudimentary data set assessing the potential roles played by the APLP gene family in the process of Alzheimer- and age-related neurodegeneration.
