Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease

Families bearing mutations in the presenilin 1 (PS1) gene develop early ons et familial Alzheimer's disease (FAD). Further, some PS1 mutants enhance se cretion of the longer form of amyloid beta protein (A beta 42). We construc ted cDNAs encoding human PS1 harboring 28 FAD-linked mutations, and examine d the effects of the expressed PS1 mutants on A beta 42 secretion in beta a myloid precursor producing COS-1 cells. All the mutants significantly enhan ced the ratio of A beta 42 to total A beta compared with wild-type PS1. How ever, the increase in A beta 42 ratio in cells with each PS1 mutation did n ot correlate with the reported age of onset of FAD caused by that mutation. These results suggest that increased A beta 42 secretion is important for the development of Alzheimer's disease (AD), but may not be the only factor contributing to the onset of AD. (C) 1999 Elsevier Science Ireland Ltd. Al l rights reserved.