Concentration-dependent modulation of amyloid-β in vivo and in vitro using the γ-secretase inhibitor, LY-450139

LY-450139 is a gamma-secretase inhibitor shown to have efficacy in multiple cellular and animal models. Paradoxically, robust elevations of plasma amyloid-beta (A beta) have been reported in dogs and humans after administration of subefficacious doses. The present study sought to further evaluate A beta responses to LY-450139 in the guinea pig, a nontransgenic model that has an A beta sequence identical to that of human. Male guinea pigs were treated with LY-450139 (0.2-60 mg/kg), and brain, cerebrospinal fluid, and plasma A beta levels were characterized at 1, 3, 6, 9, and 14 h postdose. Low doses significantly elevated plasma A beta levels at early time points, with return to baseline within hours. Higher doses inhibited A beta levels in all compartments at early time points, but elevated plasma A beta levels at later time points. To determine whether this phenomenon occurs under steady-state drug exposure, guinea pigs were implanted with subcutaneous minipumps delivering LY-450139 (0.3-30 mg/kg/day) for 5 days. Plasma A beta was significantly inhibited at 10-30 mg/kg/day, but significantly elevated at 1 mg/kg/day. To further understand the mechanism of A beta elevation by LY-450139, H4 cells overexpressing the Swedish mutant of amyloid-precursor protein and a mouse embryonic stem cell-derived neuronal cell line were studied. In both cellular models, elevated levels of secreted A beta were observed at subefficacious concentrations, whereas dose-responsive inhibition was observed at higher concentrations. These results suggest that LY-450139 modulates the gamma-secretase complex, eliciting A beta lowering at high concentrations but A beta elevation at low concentrations.