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Cell Rep. 2016 Mar 8;14(9):2127-2141. doi: 10.1016/j.celrep.2016.01.076. Epub 2016 Feb 25.

Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein.

Author information

1
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.
2
Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland.
3
Department of Physical Chemistry, School of Chemistry, Madurai Kamaraj University, Tamil Nadu 625002, Madurai, India.
4
Biomedical Center, Ludwig-Maximilians-University, 81337 Munich, Germany.
5
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
6
Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany; Life & Brain, 53127 Bonn, Germany.
7
Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany.
8
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.
9
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.

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.

KEYWORDS:

APP; Alzheimer disease; BACE; Neuregulin; amyloid; membrane trafficking; molecular dynamics; secretase; subcellular compartmentalization

PMID:
26923602
DOI:
10.1016/j.celrep.2016.01.076
[Indexed for MEDLINE]
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