Alzheimer's disease-linked mutation of presenilin 2 (N1411-PS2) drastically lowers APPα secretion:: Control by the proteasome

Most of early onset familial forms of Alzheimer's disease (FAD) are due to inherited mutations located on two homologous proteins, presenilins 1 and 2 (PS1 and PS2) encoded by chromosomes 14 and 1, respectively. Here we show that the expression of wild type (wt)-PS2 in human HEK293 cells increases the production of the physiological alpha-secretase-derived product, APP alpha. By contrast, APP alpha secretion is drastically reduced in cells expressing the FAD-linked N141I-PS2. We establish that wt-PS2, N141I-PS2 and their C-terminal maturation fragment are degraded by the enzymatic multicatalytic complex, proteasome. Interestingly, two selective proteasome inhibitors, Z-IE(Ot-Bu)A-Leucinal and lactacystin potentiate the APP alpha secretion observed in wtPS2-expressing cells and further amplify the N141I-PS2-induced decrease in APP alpha production. By contrast, a series of pharmacological agents unable to affect the proteasome do not modify PS2 immunoreactivities and APP alpha recoveries. Altogether, our data indicate that: 1) wtPS2 positively modulates the alpha-secretase physiological pathway of beta APP maturation in human cells; 2) N141I mutation on PS2 drastically lowers the secretion of APP alpha; 3) Proteasome inhibitors prevent the degradation of wtPS2, N141I-PS2 and their C-terminal maturation product. This protection against proteasomal degradation directly modulates the APP alpha secretion response elicited by wt- and FAD-linked PS2 expression in human HEK293 cells. (C) 1998 Academic Press.