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 (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 β-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.
authors.affiliation: Systems and Cell Biology of Neurodegeneration, Institute of Regenerative Medicine, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Graduate Program in Neuroscience, Neuroscience Center Zurich, 8057 Zurich, Switzerland; Graduate Program of the Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Saoussen
authors.initials: S
authors.lastname: Ben Halima
authors.affiliation: Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Sabyashachi
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Department of Physical Chemistry, School of Chemistry, Madurai Kamaraj University, Tamil Nadu 625002, Madurai, India.
authors.forename: K Muruga Poopathi
authors.initials: KMP
authors.lastname: Raja
authors.affiliation: Biomedical Center, Ludwig-Maximilians-University, 81337 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Willem
authors.affiliation: Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Baici
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Simons
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany; Life & Brain, 53127 Bonn, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Brüstle
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Koch
authors.affiliation: Biomedical Center, Ludwig-Maximilians-University, 81337 Munich, Germany; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
authors.affiliation: Systems and Cell Biology of Neurodegeneration, Institute of Regenerative Medicine, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Graduate Program in Neuroscience, Neuroscience Center Zurich, 8057 Zurich, Switzerland; Graduate Program of the Zurich Center for Integrative Human Physiology, University of Zurich, 8057 Zurich, Switzerland. Electronic address: rajendran@bli.uzh.ch.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rajendran
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D007700:Kinetics; D051379:Mice; D056004:Molecular Dynamics Simulation; D020890:Neuregulin-1 / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D013379:Substrate Specificity
chemical_list: D016564:Amyloid beta-Protein Precursor; C094131:NRG1 protein, human; D020890:Neuregulin-1; C414614:OM99-2; D009842:Oligopeptides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: APP; Alzheimer disease; BACE; Neuregulin; amyloid; membrane trafficking; molecular dynamics; secretase; subcellular compartmentalization