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  • Title: Alzheimer's disease-linked mutation of presenilin 2 (N141I-PS2) drastically lowers APPalpha secretion: control by the proteasome.
    Author: Marambaud P, Alves da Costa C, Ancolio K, Checler F.
    Journal: Biochem Biophys Res Commun; 1998 Nov 09; 252(1):134-8. PubMed ID: 9813158.
    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 alpha-secretase-derived product, APPalpha. By contrast, APPalpha 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 APPalpha secretion observed in wtPS2-expressing cells and further amplify the N141I-PS2-induced decrease in APPalpha production. By contrast, a series of pharmacological agents unable to affect the proteasome do not modify PS2 immunoreactivities and APPalpha recoveries. Altogether, our data indicate that: 1) wtPS2 positively modulates the alpha-secretase physiological pathway of betaAPP maturation in human cells; 2) N141I mutation on PS2 drastically lowers the secretion of APPalpha; 3) Proteasome inhibitors prevent the degradation of wtPS2, N141I-PS2 and their C-terminal maturation product. This protection against proteasomal degradation directly modulates the APPalpha secretion response elicited by wt- and FAD-linked PS2 expression in human HEK293 cells.
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