Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein
Cell Rep. 2016 Mar 8;14(9):2127-41
Saoussen Ben Halima
K. Muruga Poopathi Raja
|Type of Publication:||Journal Article|
Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic b-amyloid (Ab) peptides produced by b- and 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-cleavage of non-amyloid substrates like Neuregulin. We report that b-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of b-secretase are higher toward non-amyloid substrates 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 cleavage 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 therapeutics without undesired side effects.