title: Characterization of insulin-degrading enzyme-mediated cleavage of Aβ in distinct aggregation states.
abstract: To enhance our understanding of the potential therapeutic utility of insulin-degrading enzyme (IDE) in Alzheimer's disease (AD), we studied in vitro IDE-mediated degradation of different amyloid-beta (Aβ) peptide aggregation states. Our findings show that IDE activity is driven by the dynamic equilibrium between Aβ monomers and higher ordered aggregates. We identify Met(35)-Val(36) as a novel IDE cleavage site in the Aβ sequence and show that Aβ fragments resulting from IDE cleavage form non-toxic amorphous aggregates. These findings need to be taken into account in therapeutic strategies designed to increase Aβ clearance in AD patients by modulating IDE activity.
authors.affiliation: Nanobiophysics Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, Universiteit Twente, Enschede, The Netherlands; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hubin
authors.affiliation: Nanobiophysics Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, Universiteit Twente, Enschede, The Netherlands.
authors.forename: Federica
authors.initials: F
authors.lastname: Cioffi
authors.affiliation: Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.affiliation: Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: nvnuland@vub.ac.be.
authors.forename: Nico A J
authors.initials: NA
authors.lastname: van Nuland
authors.affiliation: Nanobiophysics Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, Universiteit Twente, Enschede, The Netherlands. Electronic address: k.broersen@utwente.nl.
authors.forename: Kerensa
authors.initials: K
authors.lastname: Broersen
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D007339:Insulysin / Q000502:physiology*; D008969:Molecular Sequence Data; D066329:Protein Aggregates
chemical_list: D016229:Amyloid beta-Peptides; D066329:Protein Aggregates; D007339:Insulysin
keywords: Aggregation; Alzheimer's disease; Amyloid-beta; Aβ cleavage; Insulin-degrading enzyme; Neprilysin