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Alzheimer's-causing mutations shift Aβ length by destabilizing γ-secretase-Aβn interactions

Maria Szaruga, Bogdan Munteanu, Sam Lismont, Sarah Veugelen, Katrien Horre, Marc Mercken, Takaomi C Saido, Natalie S Ryan, Tatjana De Vos (UGent) , Savvas Savvides (UGent) , et al.
(2017) CELL. 170(3). p.443-456
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Abstract
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.
Keywords
AMYLOID PRECURSOR PROTEIN, TRANSMEMBRANE DOMAIN, TERMINAL FRAGMENT, SUBSTRATE DOCKING, DISEASE MUTATIONS, MEMBRANE, PEPTIDE, MODULATORS, A-BETA-42, CONFORMATION

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MLA
Szaruga, Maria, et al. “Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions.” CELL, vol. 170, no. 3, 2017, pp. 443–56, doi:10.1016/j.cell.2017.07.004.
APA
Szaruga, M., Munteanu, B., Lismont, S., Veugelen, S., Horre, K., Mercken, M., … Chavez-Gutierrez, L. (2017). Alzheimer’s-causing mutations shift Aβ length by destabilizing γ-secretase-Aβn interactions. CELL, 170(3), 443–456. https://doi.org/10.1016/j.cell.2017.07.004
Chicago author-date
Szaruga, Maria, Bogdan Munteanu, Sam Lismont, Sarah Veugelen, Katrien Horre, Marc Mercken, Takaomi C Saido, et al. 2017. “Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions.” CELL 170 (3): 443–56. https://doi.org/10.1016/j.cell.2017.07.004.
Chicago author-date (all authors)
Szaruga, Maria, Bogdan Munteanu, Sam Lismont, Sarah Veugelen, Katrien Horre, Marc Mercken, Takaomi C Saido, Natalie S Ryan, Tatjana De Vos, Savvas Savvides, Rodrigo Gallardo, Joost Schymkowitz, Frederic Rousseau, Nick C Fox, Carsten Hopf, Bart De Strooper, and Lucia Chavez-Gutierrez. 2017. “Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions.” CELL 170 (3): 443–456. doi:10.1016/j.cell.2017.07.004.
Vancouver
1.
Szaruga M, Munteanu B, Lismont S, Veugelen S, Horre K, Mercken M, et al. Alzheimer’s-causing mutations shift Aβ length by destabilizing γ-secretase-Aβn interactions. CELL. 2017;170(3):443–56.
IEEE
[1]
M. Szaruga et al., “Alzheimer’s-causing mutations shift Aβ length by destabilizing γ-secretase-Aβn interactions,” CELL, vol. 170, no. 3, pp. 443–456, 2017.
@article{8529485,
  abstract     = {{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.}},
  author       = {{Szaruga, Maria and Munteanu, Bogdan and Lismont, Sam and Veugelen, Sarah and Horre, Katrien and Mercken, Marc and Saido, Takaomi C and Ryan, Natalie S and De Vos, Tatjana and Savvides, Savvas and Gallardo, Rodrigo and Schymkowitz, Joost and Rousseau, Frederic and Fox, Nick C and Hopf, Carsten and De Strooper, Bart and Chavez-Gutierrez, Lucia}},
  issn         = {{0092-8674}},
  journal      = {{CELL}},
  keywords     = {{AMYLOID PRECURSOR PROTEIN,TRANSMEMBRANE DOMAIN,TERMINAL FRAGMENT,SUBSTRATE DOCKING,DISEASE MUTATIONS,MEMBRANE,PEPTIDE,MODULATORS,A-BETA-42,CONFORMATION}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{443--456}},
  title        = {{Alzheimer's-causing mutations shift Aβ length by destabilizing γ-secretase-Aβn interactions}},
  url          = {{http://dx.doi.org/10.1016/j.cell.2017.07.004}},
  volume       = {{170}},
  year         = {{2017}},
}
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