MUTANT PRESENILINS OF ALZHEIMERS-DISEASE INCREASE PRODUCTION OF 42-RESIDUE AMYLOID BETA-PROTEIN IN BOTH TRANSFECTED CELLS AND TRANSGENIC MICE

The mechanism by which mutations in the presenilin (PS) genes cause th e most aggressive form of early-onset Alzheimer's disease (AD) is unkn own, but fibroblasts from mutation carriers secrete increased levels o f the amyloidogenic A beta(42) peptide, the main component of AD plaqu es. We established transfected cell and transgenic mouse models that c oexpress human PS and amyloid beta-protein precursor (APP) genes and a nalyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP le vels, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta(42) secretion in all mutant clones. Likewise, mutan t but not wildtype PS1 transgenic mice showed significant overproducti on of A beta(42) in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta(42) increase did not corre late with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta(42) production, thus promoting cerebral beta-am yloidosis.