Γ-secretase modulators do not induce Aβ-rebound and accumulation of β-C-terminal fragment.

gamma-secretase inhibitors (GSIs) have been developed to reduce amyloid-beta (A beta) production for the treatment of Alzheimers disease by inhibiting the cleavage of amyloid precursor protein (APP). However, cross-inhibitory activity on the processing of Notch can cause adverse reactions. To avoid these undesirable effects, ?-secretase modulators (GSMs) are being developed to selectively reduce toxic A beta production without perturbing Notch signaling. As it is also known that GSIs can cause a paradoxical increase of plasma A beta over the baseline after a transient reduction (known as A beta-rebound), we asked if GSMs would cause a similar rebound and what the potential mechanism might be. Our studies were performed with one GSI (LY-450139) and two chemically distinct GSMs. Although LY-450139 caused A beta-rebound as expected in rat plasma, the two GSMs did not. Inhibition of APP processing by LY-450139 induced an accumulation of ?-secretase substrates, a- and beta-C-terminal fragments of APP, but neither GSM caused such an accumulation. In conclusion, we discover that GSMs, unlike GSIs, do not cause A beta-rebound, possibly because of the lack of accumulation of beta-C-terminal fragments. GSMs may be superior to GSIs in the treatment of Alzheimers disease not only by sparing Notch signaling but also by avoiding A beta-rebound.