Characterization of insulin-degrading enzyme-mediated cleavage of Aβ in distinct aggregation states

  • Biochim Biophys Acta. 2016 Jun;1860(6):1281-90. doi: 10.1016/j.bbagen.2016.03.010.
Ellen Hubin  1 ,  Federica Cioffi  2 ,  Jef Rozenski  3 ,  Nico A J van Nuland  4 ,  Kerensa Broersen  5
Affiliations
  • 1. 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.
  • 2. Nanobiophysics Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, Universiteit Twente, Enschede, The Netherlands.
  • 3. Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
  • 4. Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: [email protected].
  • 5. Nanobiophysics Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, Universiteit Twente, Enschede, The Netherlands. Electronic address: [email protected].
PMID: 26968463 DOI: 10.1016/j.bbagen.2016.03.010
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.

Keywords
Aggregation; Alzheimer's disease; Amyloid-beta; Aβ cleavage; Insulin-degrading enzyme; Neprilysin.