Specific Inhibition of bSe cretase Processing of the Alzheimer Disease Amyloid Precursor Protein Graphical

Graphical Abstract Highlights d The AD-linked protease BACE1 cleaves APP to produce toxic b-amyloid peptides d BACE1 also cleaves the non-amyloid substrates NRG1 and L1 d BACE1 cleavage of NRG1 and L1 is endocytosis-independent, unlike the cleavage of APP d The endosomally targeted BACE1 inhibitor spares NRG1 and L1 but inhibits APP processing In Brief Ben Halima et al. demonstrate the feasibility of designing drugs targeting the Alzheimer-related enzyme BACE1 without affecting its physiological function. Using structural, biochemical, and cellular approaches, they show that BACE1 inhibitors can be designed to specifically inhibit its disease-causing activity, enhancing their potential as therapeutics without undesired side effects. Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic b-amyloid (Ab) peptides produced by band g-secretase-mediated cleavage of the amyloid precursor protein (APP). b-secretase inhibitors reduce Ab levels, but mechanism-based side effects arise because they also inhibit b-cleav-age of non-amyloid substrates like Neuregulin. We report that b-secretase has a higher affinity for Neure-gulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of b-secretase are higher toward non-amyloid sub-strates than toward APP. We show that non-amyloid substrates are processed by b-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal b-secretase by an endosomally targeted b-secretase inhibitor, which blocked cleav-age of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. b-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeu-tics without undesired side effects.