Lili Zhang, Lixin Song, E. Parker
Mar 26, 1999
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Journal
The Journal of Biological Chemistry
Abstract
The calpain inhibitorN-acetyl-leucyl-leucyl-norleucinal (ALLN) has been reported to have complex effects on the production of the β-amyloid peptide (Aβ). In this study, the effects of ALLN on the processing of the amyloid precursor protein (APP) to Aβ were examined in 293 cells expressing APP or the C-terminal 100 amino acids of APP (C100). In cells expressing APP or low levels of C100, ALLN increased Aβ40 and Aβ42 secretion at low concentrations, decreased Aβ40 and Aβ42 secretion at high concentrations, and increased cellular levels of C100 in a concentration-dependent manner by inhibiting C100 degradation. Low concentrations of ALLN increased Aβ42 secretion more dramatically than Aβ40 secretion. ALLN treatment of cells expressing high levels of C100 did not alter cellular C100 levels and inhibited Aβ40 and Aβ42 secretion with similar IC50 values. These results suggest that C100 can be processed both by γ-secretase and by a degradation pathway that is inhibited by low concentrations of ALLN. The data are consistent with inhibition of γ-secretase by high concentrations of ALLN but do not support previous assertions that ALLN is a selective inhibitor of the γ-secretase producing Aβ40. Rather, Aβ42 secretion may be more dependent on C100 substrate concentration than Aβ40 secretion.