Plasma proteomics of mice treated with BACE inhibitors

The Beta-secretase BACE1 is a central drug target for Alzheimer’s disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological BACE2 substrates and functions in vivo. To discover potential BAC2 substrates in plasma, mice were treated with a non-specific BACE inhibitor (Cpd89) and a BACE1 preferring inhibitor (LY2811376). Plasma proteomics using DIA showed a reduced abundance of soluble FLT4 (sVEGFR3) for the non-specific inhbtor but not for the BACE1 preferring inhibitor. Conclusively, sVEGFR3 is a potential marker for BACE2 inhibition in plasma.