RT Journal Article
SR Electronic
T1 Concentration-Dependent Modulation of Amyloid-β in Vivo and in Vitro Using the γ-Secretase Inhibitor, LY-450139
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 924
OP 933
DO 10.1124/jpet.106.110700
VO 319
IS 2
A1 Lanz, Thomas A.
A1 Karmilowicz, Michael J.
A1 Wood, Kathleen M.
A1 Pozdnyakov, Nikolay
A1 Du, Ping
A1 Piotrowski, Mary A.
A1 Brown, Tracy M.
A1 Nolan, Charles E.
A1 Richter, Karl E. G.
A1 Finley, James E.
A1 Fei, Qing
A1 Ebbinghaus, Charles F.
A1 Chen, Yuhpyng L.
A1 Spracklin, Douglas K.
A1 Tate, Barbara
A1 Geoghegan, Kieran F.
A1 Lau, Lit-Fui
A1 Auperin, David D.
A1 Schachter, Joel B.
YR 2006
UL http://jpet.aspetjournals.org/content/319/2/924.abstract
AB LY-450139 is a γ-secretase inhibitor shown to have efficacy in multiple cellular and animal models. Paradoxically, robust elevations of plasma amyloid-β (Aβ) have been reported in dogs and humans after administration of subefficacious doses. The present study sought to further evaluate Aβ responses to LY-450139 in the guinea pig, a nontransgenic model that has an Aβ 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 Aβ levels were characterized at 1, 3, 6, 9, and 14 h postdose. Low doses significantly elevated plasma Aβ levels at early time points, with return to baseline within hours. Higher doses inhibited Aβ levels in all compartments at early time points, but elevated plasma Aβ 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 Aβ was significantly inhibited at 10–30 mg/kg/day, but significantly elevated at 1 mg/kg/day. To further understand the mechanism of Aβ 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 Aβ were observed at subefficacious concentrations, whereas dose-responsive inhibition was observed at higher concentrations. These results suggest that LY-450139 modulates the γ-secretase complex, eliciting Aβ lowering at high concentrations but Aβ elevation at low concentrations. The American Society for Pharmacology and Experimental Therapeutics