Identification and Preclinical Pharmacology of the -Secretase Modulator BMS-869780
BMS-869780 increased the levels of the shorter peptides Aβ1-38 and Aβ1-37. (a) Top panel: an equimolar mix of synthetic peptides Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40, [15N]-Aβ1-40, and Aβ1-42 was evaluated by MALDI-TOF mass spectrometry. H4-APPsw cell cultures were treated with vehicle (0.1% DMSO—middle panel) or BMS-869780 (100 nM—bottom panel), [15N]-Aβ1-40 was added, and Aβ peptides were immunoprecipitated and evaluated by MALDI-TOF mass spectrometry. (b) H4-APPsw cell cultures were treated with BMS-869780 or DMSO vehicle. Aβ peptides were separated by gel electrophoresis in the presence of urea and detected by western blotting. Under these conditions, higher molecular weight Aβ peptides exhibit greater gel mobility. Lane 1: an equimolar mix of synthetic peptides Aβ1-38, Aβ1-40, and Aβ1-42. Lane 2: DMSO vehicle-treated cell culture. Lanes 3–6: Cell cultures treated with BMS-869780 at final concentrations of 100, 10, 1 and 0.1 nM, respectively.
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