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. 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

Ellen Hubin  1 , Federica Cioffi  2 , Jef Rozenski  3 , Nico A J van Nuland  4 , Kerensa Broersen  5
Affiliations

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

Ellen Hubin et al. Biochim Biophys Acta. 2016 Jun.

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.

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