期刊
CELL
卷 170, 期 3, 页码 443-456出版社
CELL PRESS
DOI: 10.1016/j.cell.2017.07.004
关键词
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资金
- Stichting Alzheimer Onderzoek (SAO) [S16013]
- Fund for Scientific Research Flanders (FWO) [G074115]
- KU Leuven, a Methusalem grant from KU Leuven [METH/14/07]
- Flemish government
- Interuniversity Attraction Poles Program of the Belgian Federal Science Policy Office [P7/16]
- Bax-Vanluffelen Chair for Alzheimer's Disease and Opening the Future of the Leuven Universiteit Fonds
- Vlaams Initiatief voor Netwerken voor Dementie Onderzoek (VIND) [135043]
- European Research Council under European Union [647458]
- University of Leuven (Industrieel Onderzoeksfonds) [OT/12/092]
- Funds for Scientific Research Flanders [G051817N]
- Flanders Agency for Innovation by Science and Technology (IWT SBO) [60839]
- Federal Office for Scientific Affairs of Belgium (Belspo), IUAP grant [P7/16]
- IUAPZAFH-ABIMAS
- ZO IV of the Ministerium fur Wissenschaft und Kunst Baden-Wurttemberg (MWK)
- European Fund for Regional Development (EFRE) [Kapitel 1222 Titelgruppe 88]
- Deutsche Forschungsgemeinschaft (DFG) [INST 874/7-1]
- IWT [SB/131289]
- Hercules foundation [AUGE/11/029]
- Brain Exit fellowship
- Janssen Pharmaceutica
- MRC [MC_PC_17116, UKDRI-1001] Funding Source: UKRI
- Medical Research Council [MC_PC_17116] Funding Source: researchfish
Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic A beta peptides. The shift in A beta 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 gamma-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer A beta peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic A beta. In contrast, E-A beta n stabilizers increase gamma-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic A beta production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the development of gamma-secretase/substrate stabilizing compounds for the prevention of AD.
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