New protease inhibitors prevent γ-secretase-mediated production of Aβ40/42 without affecting Notch cleavage

We have designed new non-peptidic potential inhibitors of gamma -secretase and examined their ability to prevent production of amyloid-beta 40 (A beta 40) and A beta 42 by human cells expressing wild-type and Swedish-mutant beta -amyloid precursor protein (beta APP). Here we identify three such agents that markedly reduce recovery of both A beta 40 and A beta 42 produced by both cell lines, and increase that of C99 and C83, the carboxy-terminal fragments of beta APP that are derived from beta -and alpha -secretase, respectively, Furthermore, we show that these inhibitors do not affect endoproteolysis of endogenous or overexpressed presenilins. These inhibitors are totally unable to affect the m Delta Enotch-1 cleavage that leads to generation of the Notch intracellular domain (NICD). These represent the first non-peptidic inhibitors that are able to prevent gamma -secretase cleavage of beta APP without affecting processing of m Delta Enotch-1 or endoproteolysis of presenilins. The distinction between these two proteolytic events, which are both prevented by disruption of presenilin genes, indicates that although they are intimately linked with beta APP and Notch maturation, presenilins are probably involved in the control of maturation processes upstream of enzymes that cleave gamma -secretase and Notch.