@article{bibcite_464, keywords = {Kinetics, Animals, Humans, Oligopeptides, Aspartic Acid Endopeptidases, Amyloid Precursor Protein Secretases, Alzheimer Disease, Mice, Substrate Specificity, Amyloid beta-Protein Precursor, Protein Processing, Post-Translational, Molecular Dynamics Simulation, Cells, Cultured, Endocytosis, Endosomes, Golgi Apparatus, Induced Pluripotent Stem Cells, Neuregulin-1, Protein Transport, Proteolysis}, author = {S. Ben Halima and S. Mishra and K. M. P. Raja and M. Willem and A. Baici and K. Simons and O. Br{\"u}stle and P. Koch and C. Haass and A. Caflisch and L. Rajendran}, title = {Specific inhibition of β-secretase processing of the Alzheimer disease amyloid precursor protein}, abstract = {

Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic \β-amyloid (A\β) peptides produced by \β- and \γ-secretase-mediated cleavage of the amyloid precursor protein (APP). \β-secretase inhibitors reduce A\β 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.

}, year = {2016}, journal = {Cell Reports}, volume = {14}, chapter = {2127}, pages = {2127-2141}, month = {2016 Mar 08}, issn = {2211-1247}, doi = {10.1016/j.celrep.2016.01.076}, language = {eng}, }