Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions
Authors: Joost Schymkowitz
Tatjana De Vos
Natalie S Ryan
Savvas N Savvides
Sarah Veugelen
Sam Lismont
Lucía Chávez-Gutiérrez
Marc Mercken
Katrien Horré
Nick C Fox
Rodrigo Gallardo
Bogdan Munteanu
Bart De Strooper
Frederic Rousseau
Maria Szaruga
Carsten Hopf
Takaomi C Saido
Journal: Cell (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Alzheimer’s disease; amyloid beta; amyloid precursor protein; enzyme thermoactivity; presenilin
Affiliations: 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., Center of Applied Research in Biomedical Mass Spectrometry, Mannheim University of Applied Sciences, 68163 Mannheim, Germany., Janssen Research & Development, Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium., Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Hirosawa Wako City, Saitama 351-0198, Japan., Dementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square, WC1N 3BG London, UK., 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., 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., 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: ., 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: .

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. 

Retracted: No

PubPeer comments:
 Thank you for putting together this paper (and pipeline). I believe there is a typo in the legend **Figure 1C** that needs to be corrected:  Seuart --  Seurat Since I don t see this article in PubMed yet, maybe this is early enough to correct the content without a formal correction? , 
 #1 Thanks for letting us know. ,