S. Ben Halima; S. Mishra; K.M.P. Raja; M. Willem; A. Baici; K. Simons; O. Brüstle; P. Koch; C. Haass; A. Caflisch; L. Rajendran

Journal: Cell Rep.
Year: 2016
Volume: 14
Issue: 9
Pages: 2127-2141
DOI: 10.1016/j.celrep.2016.01.076
Type of Publication: Journal Article

Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cells, Cultured; Endocytosis; Endosomes; Golgi Apparatus; Humans; Induced Pluripotent Stem Cells; Kinetics; Mice; Molecular Dynamics Simulation; Neuregulin-1; Oligopeptides; Protein Processing, Post-Translational; Protein Transport; Proteolysis; Substrate Specificity


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