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Cell. 2017 Jul 27;170(3):443-456.e14. doi: 10.1016/j.cell.2017.07.004.

Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions.

Author information

1
KU Leuven-VIB Center for Brain & Disease Research, VIB, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Institute for Neuroscience and Disease, KU Leuven, 3000 Leuven, Belgium.
2
Center of Applied Research in Biomedical Mass Spectrometry, Mannheim University of Applied Sciences, 68163 Mannheim, Germany.
3
Janssen Research & Development, Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
4
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Hirosawa Wako City, Saitama 351-0198, Japan.
5
Dementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square, WC1N 3BG London, UK.
6
Ghent University, Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, 9000 Ghent, Belgium; Center for Inflammation Research, VIB-UGent Technologiepark 927, 9052 Ghent, Belgium.
7
KU Leuven-VIB Center for Brain & Disease Research, VIB, 3000 Leuven, Belgium; Department of Cellular and Molecular Medicine, University of Leuven, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
8
KU Leuven-VIB Center for Brain & Disease Research, VIB, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Institute for Neuroscience and Disease, KU Leuven, 3000 Leuven, Belgium; Dementia Research Institute UK, University College London, Queen Square, WC1N 3BG London, UK. Electronic address: Bart.DeStrooper@cme.vib-kuleuven.be.
9
KU Leuven-VIB Center for Brain & Disease Research, VIB, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Institute for Neuroscience and Disease, KU Leuven, 3000 Leuven, Belgium. Electronic address: Lucia.ChavezGutierrez@cme.vib-kuleuven.be.

Abstract

Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic Aβ peptides. The shift in Aβ length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential γ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Aβ peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic Aβ. In contrast, E-Aβn stabilizers increase γ-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic Aβ production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the development of γ-secretase/substrate stabilizing compounds for the prevention of AD.

KEYWORDS:

Alzheimer’s disease; amyloid beta; amyloid precursor protein; enzyme thermoactivity; presenilin; protein thermosability; γ-secretase

PMID:
28753424
DOI:
10.1016/j.cell.2017.07.004
[Indexed for MEDLINE]
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