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

Ellen Hubin, Federica Cioffi, Jef Rozenski, Nico A.J. van Nuland^*, Kerensa Broersen^*

^*Corresponding author for this work

Nanobiophysics

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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 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.

Original language	English
Pages (from-to)	1281-1290
Number of pages	10
Journal	Biochimica et biophysica acta. General subjects
Volume	1860
Issue number	6
DOIs	https://doi.org/10.1016/j.bbagen.2016.03.010
Publication status	Published - 1 Jun 2016

Keywords

Aggregation
Alzheimer's disease
Amyloid-beta
Aβ cleavage
Insulin-degrading enzyme
Neprilysin
2023 OA procedure

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10.1016/j.bbagen.2016.03.010

characterizationFinal published version, 1.31 MBLicence: Taverne

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title = "Characterization of insulin-degrading enzyme-mediated cleavage of Aβ in distinct aggregation states",

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 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.",

keywords = "Aggregation, Alzheimer's disease, Amyloid-beta, Aβ cleavage, Insulin-degrading enzyme, Neprilysin, 2023 OA procedure",

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AU - Broersen, Kerensa

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KW - Alzheimer's disease

KW - Amyloid-beta

KW - Aβ cleavage

KW - Insulin-degrading enzyme

KW - Neprilysin

KW - 2023 OA procedure

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

Abstract

Keywords

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