Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein

Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic beta-amyloid (Ab) peptides produced by beta- and gamma-secretase-mediated cleavage of the amyloid precursor protein (APP). beta-secretase inhibitors reduce A beta levels, but mechanism-based side effects arise because they also inhibit beta-cleavage of non-amyloid substrates like Neuregulin. We report that beta-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of beta-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by beta-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal beta-secretase by an endosomally targeted beta-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. beta-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects.