The major component of senile plaques found in the brains of Alzheimer!s disease patients is the b-amyloid peptide, which is derived from a larger amyloid precursor protein (bAPP). Early-onset familial Alzheimer!s disease has been shown to correlate with mutations in four genes, including the bAPP gene. We are studying an bAPP-related gene,
apl-1, in C. elegans. To identify genes that interact with
apl-1, transgenic lines in which an
apl-1 cDNA is under the control of a neural specific promoter (VAMP) were generated. These transgenic strains, NY2012, NY2013, and NY2014, were confirmed by Western blot analysis to overexpress APL-1. The transgenic animals have defects in movement; specifically, they move slowly and are sluggish. To look for genes that interact with
apl-1, we mutagenized transgenic animals with EMS and looked for reversion of the sluggish phenotype. After screening about 1,500 F1 animals, we found two strains that suppress the sluggish phenotype. One strain shows a hyperactive phenotype, while the other strain shows wild-type movement. We are currently mapping these possible suppressor genes. APL-1 does not contain the b-amyloid peptide. To determine whether production of b-amyloid peptide has deleterious effects in C. elegans, we generated transgenic strains containing a mouse APP cDNA under the control of the VAMP promoter; the transgene was integrated by UV irradiation. The strains were backcrossed into a wild-type background to remove unlinked mutations. We are currently characterizing the phenotype of these transgenic lines, and will determine whether the b-amyloid peptide is produced.