Specific inhibition of β-secretase processing of the Alzheimer disease amyloid precursor protein

TitleSpecific inhibition of β-secretase processing of the Alzheimer disease amyloid precursor protein
Publication TypeJournal Article
Year of Publication2016
AuthorsBen Halima S., Mishra S., Raja K.MP, Willem M., Baici A., Simons K., Brüstle O., Koch P., Haass C., Caflisch A., Rajendran L.
JournalCell Reports
Start Page2127
Date Published2016 Mar 08
Type of ArticleResearch Article
KeywordsAlzheimer 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.



Alternate JournalCell Rep.
PubMed ID26923602
Highlight Role: 
Drug Design