Alzheimer's Disease-Linked Mutation of Presenilin 2 (N141I-PS2) Drastically Lowers APPα Secretion: Control by the Proteasome

Abstract

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 α-secretase-derived product, APPα. By contrast, APPα 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 APPα secretion observed in wtPS2-expressing cells and further amplify the N141I-PS2-induced decrease in APPα production. By contrast, a series of pharmacological agents unable to affect the proteasome do not modify PS2 immunoreactivities and APPα recoveries. Altogether, our data indicate that: 1) wtPS2 positively modulates the α-secretase physiological pathway of βAPP maturation in human cells; 2) N141I mutation on PS2 drastically lowers the secretion of APPα; 3) Proteasome inhibitors prevent the degradation of wtPS2, N141I-PS2 and their C-terminal maturation product. This protection against proteasomal degradation directly modulates the APPα secretion response elicited by wt- and FAD-linked PS2 expression in human HEK293 cells.