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Biochim Biophys Acta. 2016 Jun;1860(6):1281-90. doi: 10.1016/j.bbagen.2016.03.010. Epub 2016 Mar 8.

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

Author information

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.

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

PMID:
26968463
DOI:
10.1016/j.bbagen.2016.03.010
[Indexed for MEDLINE]

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