Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice

Abstract

The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic Aβ₄₂ peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid β-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, α- and β-secretase activity and Aβ production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in Aβ₄₂ secretion in all mutant clones. Likewise, mutant but not wild-type PS1 transgenic mice showed significant overproduction of Aβ₄₂ in the brain, and this effect was detectable as early as 2–4 months of age. Different PS mutations had differential effects on Aβ generation. The extent of Aβ₄₂ increase did not correlate with presenilin expression levels. Our data demonstrate that the preseniiin mutations cause a dominant gain of function and may induce AD by enhancing Aβ₄₂ production, thus promoting cerebral β-amyloidosis.