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

It has been hypothesized that different C-terminus of β-amyloid peptide (Aβ) may be generated by different γ-secretase activities. Recently, we have identified a new ζ-cleavage site at Aβ46, leading to an important finding that the C-terminus of Aβ is produced by a series of sequential cleavages. This finding prompted us to examine the effects of the known γ-secretase inhibitors on different steps of the γ-secretase-mediated sequential cleavages and specifically their effects on the formation and turnover of the intermediate Aβ46. 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 Aβ40/42 by inhibiting the formation of the intermediate Aβ46. However, most of the other inhibitors show no inhibitory effect on the formation of the intermediate Aβ46, but rather inhibit the turnover of Aβ46, 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 Aβ46, but rather modulate the ratio of secreted Aβ at a step after the formation of Aβ40 and Aβ42. Thus, our data strongly suggest that the multi-sequential intramembrane cleavages of amyloid precursor protein C (APP) are likely catalyzed by the same γ-secretase.