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

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.
PMID
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Authors

Mayor MeshTerms
Keywords

Alzheimer’s disease

amyloid beta

amyloid precursor protein

enzyme thermoactivity

presenilin

protein thermosability

γ-secretase

Journal Title cell
Publication Year Start




PMID- 28753424
OWN - NLM
STAT- In-Process
DA  - 20170728
LR  - 20170728
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Linking)
VI  - 170
IP  - 3
DP  - 2017 Jul 27
TI  - Alzheimer's-Causing Mutations Shift Abeta Length by Destabilizing
      gamma-Secretase-Abetan Interactions.
PG  - 443-456.e14
LID - S0092-8674(17)30811-5 [pii]
LID - 10.1016/j.cell.2017.07.004 [doi]
AB  - Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid
      precursor protein (APP) lead to production of longer amyloidogenic Abeta
      peptides. The shift in Abeta 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 Abeta peptides. Similarly, destabilization
      of wild-type E-S complexes by temperature, compounds, or detergent promotes
      release of amyloidogenic Abeta. In contrast, E-Abetan stabilizers increase
      gamma-secretase processivity. Our work presents a unifying model for how PSEN or 
      APP mutations enhance amyloidogenic Abeta 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.
CI  - Copyright (c) 2017. Published by Elsevier Inc.
FAU - Szaruga, Maria
AU  - Szaruga M
AD  - 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.
FAU - Munteanu, Bogdan
AU  - Munteanu B
AD  - Center of Applied Research in Biomedical Mass Spectrometry, Mannheim University
      of Applied Sciences, 68163 Mannheim, Germany.
FAU - Lismont, Sam
AU  - Lismont S
AD  - 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.
FAU - Veugelen, Sarah
AU  - Veugelen S
AD  - 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.
FAU - Horre, Katrien
AU  - Horre K
AD  - 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.
FAU - Mercken, Marc
AU  - Mercken M
AD  - Janssen Research & Development, Division of Janssen Pharmaceutica NV, 2340
      Beerse, Belgium.
FAU - Saido, Takaomi C
AU  - Saido TC
AD  - Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Hirosawa 
      Wako City, Saitama 351-0198, Japan.
FAU - Ryan, Natalie S
AU  - Ryan NS
AD  - Dementia Research Centre, Department of Neurodegenerative Disease, University
      College London, Queen Square, WC1N 3BG London, UK.
FAU - De Vos, Tatjana
AU  - De Vos T
AD  - 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.
FAU - Savvides, Savvas N
AU  - Savvides SN
AD  - 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.
FAU - Gallardo, Rodrigo
AU  - Gallardo R
AD  - 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.
FAU - Schymkowitz, Joost
AU  - Schymkowitz J
AD  - 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.
FAU - Rousseau, Frederic
AU  - Rousseau F
AD  - 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.
FAU - Fox, Nick C
AU  - Fox NC
AD  - Dementia Research Centre, Department of Neurodegenerative Disease, University
      College London, Queen Square, WC1N 3BG London, UK.
FAU - Hopf, Carsten
AU  - Hopf C
AD  - Center of Applied Research in Biomedical Mass Spectrometry, Mannheim University
      of Applied Sciences, 68163 Mannheim, Germany.
FAU - De Strooper, Bart
AU  - De Strooper B
AD  - 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:
      [email protected]
FAU - Chavez-Gutierrez, Lucia
AU  - Chavez-Gutierrez L
AD  - 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:
      [email protected]
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - amyloid beta
OT  - amyloid precursor protein
OT  - enzyme thermoactivity
OT  - presenilin
OT  - protein thermosability
OT  - gamma-secretase
EDAT- 2017/07/29 06:00
MHDA- 2017/07/29 06:00
CRDT- 2017/07/29 06:00
PHST- 2016/12/19 [received]
PHST- 2017/04/06 [revised]
PHST- 2017/07/06 [accepted]
AID - S0092-8674(17)30811-5 [pii]
AID - 10.1016/j.cell.2017.07.004 [doi]
PST - ppublish
SO  - Cell. 2017 Jul 27;170(3):443-456.e14. doi: 10.1016/j.cell.2017.07.004.