BETA-AMYLOID PRECURSOR-LIKE GENE IN C. ELEGANS

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Deposition of dense plaques and the presence of neurofibrillary tangles are two postmortem criteria used in the definitive diagnosis of Alzheimer's disease. The major component of the dense plaques is an about 40 amino acid beta- amyloid peptide that is derived from a larger amyloid protein precursor (APP) . Two APP-related genes, which encode proteins with extensive sequence homology to APP, have been found in humans, and are members of the APP family of genes; these APP-related genes, however, do not encode the beta-amyloid peptide. Inactivation of a Drosophila APP- related gene results in behavioral deficits that can be partially rescued by a human APP transgene, suggesting that APP and APP-related proteins may have a conserved function through evolution that is independent of the beta-amyloid peptide. The normal function of APP and the APP-related proteins are still poorly understood. We are interested in studying the function of APP, and are approaching this problem by identifying APP- related genes in a simple model system, the nematode Caenorhabditis elegans. C. eiegans has the experimental advantages of being easy to manipulate genetically and molecularly. We have identified a C. eleqans gene, apl-1, that encodes an APP-related protein. The putative translation product of apl-1 has strong sequence homology with the APP family proteins. We have characterized an apl-1 cDNA, sequenced and determined the chromosomal location of the apl-I gene, and begun to generate antibodies against the APL-1 protein and its different domains. We propose to 1) identify mutations in the apl-I gene by transposon-insertion mutagenesis; 2) determine a function for APL-1 by behavioral and morphological assays; 3) identify genes that interact with apl-I by suppressor analysis; and 4) determine the effect of overexpression of apl-1. Characterization of apl-1 will yield insights into the function of this APP-related protein, and will identify genes that interact with apl-1. Furthermore, determining a function for the C. elegans APL-1 protein is likely to give clues into the function and regulation of APP in higher animals, such as man.