ALZHEIMERS-DISEASE-LINKED MUTATION OF PRESENILIN-2 (N1411-PS2) DRASTICALLY LOWERS APP-ALPHA SECRETION - CONTROL BY THE PROTEASOME

Most of early onset familial forms of Alzheimer's disease (FAD) are du e to inherited mutations located on two homologous proteins, presenili ns 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 HEK2 93 cells increases the production of the physiological alpha-secretase -derived product, APP alpha. By contrast, APP alpha secretion is drast ically reduced in cells expressing the FAD-linked N141I-PS2. We establ ish that wt-PS2, N141I-PS2 and their C-terminal maturation fragment ar e degraded by the enzymatic multicatalytic complex, proteasome. Intere stingly, two selective proteasome inhibitors, Z-IE(Ot-Bu)A-Leucinal an d lactacystin potentiate the APP alpha secretion observed in wtPS2-exp ressing cells and further amplify the N141I-PS2-induced decrease in AP P alpha production. By contrast, a series of pharmacological agents un able to affect the proteasome do not modify PS2 immunoreactivities and APP alpha recoveries. Altogether, our data indicate that: 1) wtPS2 po sitively modulates the alpha-secretase physiological pathway of beta A PP maturation in human cells; 2) N141I mutation on PS2 drastically low ers the secretion of APP alpha; 3) Proteasome inhibitors prevent the d egradation of wtPS2, N141I-PS2 and their C-terminal maturation product . This protection against proteasomal degradation directly modulates t he APP alpha secretion response elicited by wt- and FAD-linked PS2 exp ression in human HEK293 cells. (C) 1998 Academic Press.