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

Ellen Hubin; Federica Cioffi; Jef Rozenski; Nico A J van Nuland; Kerensa Broersen

doi:10.1016/j.bbagen.2016.03.010

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. Epub 2016 Mar 8.

Authors

Ellen Hubin¹, Federica Cioffi², Jef Rozenski³, Nico A J van Nuland⁴, Kerensa Broersen⁵

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: nvnuland@vub.ac.be.
⁵ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Amyloid beta-Peptides / chemistry*
Insulysin / physiology*
Molecular Sequence Data
Protein Aggregates*

Substances

Amyloid beta-Peptides
Protein Aggregates
Insulysin