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

Publication date: 27 July 2017
Source:Cell, Volume 170, Issue 3
Author(s): Maria Szaruga, Bogdan Munteanu, Sam Lismont, Sarah Veugelen, Katrien Horré, Marc Mercken, Takaomi C. Saido, Natalie S. Ryan, Tatjana De Vos, Savvas N. Savvides, Rodrigo Gallardo, Joost Schymkowitz, Frederic Rousseau, Nick C. Fox, Carsten Hopf, Bart De Strooper, Lucía Chávez-Gutiérrez
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.

Graphical abstract

Teaser

Sequential γ-secretase cuts on amyloid precursor protein (APP) generates progressively less stable enzyme-substrate (E-S) complexes. Alzheimer's disease–causing mutations destabilize E-S complexes and thereby enhance amyloidogenic Aβ production.


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