Plasma proteomics of BACE1, 2, and double KO mice

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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. Here, we performed glycoprotein enrichment and subsequent discovery proteomics to identify substrates of the protease BACE2 in plasma of mice. Therefore, we analysed plasma from BACE2 KO, BACE1/2 double KO and WT controls, as well as BACE1 KO with a separate WT control. Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3/FLT4. Thus, sVEGFR3 represents a pharmacodynamic plasma marker for BACE2 activity in vivo.