The same γ-secretase accounts for the multiple intramembrane cleavages of APP

It has been hypothesized that different C-terminus of beta-amyloid peptide (A beta) may be generated by different gamma-secretase activities. Recently, we have identified a new zeta-cleavage site at A beta 46, leading to an important finding that the C-terminus of A beta is produced by a series of sequential cleavages. This finding prompted us to examine the effects of the known gamma-secretase inhibitors on different steps of the gamma-secretase-mediated sequential cleavages and specifically their effects on the formation and turnover of the intermediate A beta(46). Our results demonstrate that some of the known inhibitors, such as L-685,458 and III-31C as well as inhibitors IV and V, inhibit the formation of secreted A beta(40/42) by inhibiting the formation of the intermediate A beta(46). However, most of the other inhibitors show no inhibitory effect on the formation of the intermediate A beta(46), but rather inhibit the turnover of A beta(46), resulting in its accumulation. In addition, the non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen and sulindac sulfide have no effect on the formation and turnover of A beta(46), but rather modulate the ratio of secreted A beta at a step after the formation of A beta(40) and A beta(42). Thus, our data strongly suggest that the multi-sequential intramembrane cleavages of amyloid precursor protein C (APP) are likely catalyzed by the same gamma-secretase.