Characterization of insulin-degrading enzyme-mediated cleavage of A beta in distinct aggregation states
Hubin, Ellen × Cioffi, Federica Rozenski, Jef van Nuland, Nico A. J Broersen, Kerensa #
Biochimica et Biophysica Acta. General Subjects vol:1860 issue:6 pages:1281-1290
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 Met35–Val36 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.