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ABSTRACT

The majority of early-onset familial Alzheimer's disease is linked to mutations in two related seven-nine transmembrane proteins (presenilin 1[PS1]) and 1 (presenilin 2), encoded by genes on chromosomes 14 and 1, repectively. To begin to examine the consequences of these mutations on the synthesis and metabolism of these proteins in vivo, and to examine the pathogenic activities of mutant polypeptides, we have produced transgenic mice expressing human (Hu) wt PS1 and Hu PS1 with a mutation (A246E) linked to FAD, using cDNA transgenes driven by the murine prion protein (PrP) promoter. Multiple lines of mice have been generated, harboring between 2 and 20 transgene copies, and expressing a single species of transgene-derived mRNA. Mice harboring either wild-type or mutant transgenes showed significant elevations in the levels of full-length 45 kDa PS1 polypeptides. Investigations to examine the effect of these mutations on the in vivo metabolsim PS1 are in progress as well as studies to examine the influences of wt and mutant PS1 on the metabolism of the amyloid precursor protein. At the time of writing, founder transgenic mice are 4 months old and first generation progeny are 2 months old without overt clinical or behavioral phentype. Investigations are in progress to determine the pathogenic consequences of these mutant proteins on the function and neuropathology of the murine CNS.