Journal article

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The Alzheimer’s disease γ-secretase generates higher 42:40 ratios for β-amyloid than for p3 peptides

  • Siegel, Gabriele Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren Campus, 8952 Schlieren, Switzerland
  • Gerber, Hermeto Foundation Eclosion, Plan-les-Ouates - Campus Biotech Innovation Park, Geneva, Switzerland - Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland - Department of Biology, University of Fribourg, Switzerland
  • Koch, Philipp Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty, Germany - LIFE and BRAIN GmbH, Bonn, Germany
  • Bruestle, Oliver Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty, Germany - LIFE and BRAIN GmbH, Bonn, Germany
  • Fraering, Patrick C. Foundation Eclosion, Plan-les-Ouates - Campus Biotech Innovation Park, Geneva, Switzerland - Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland
  • Rajendran, Lawrence Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren Campus, 8952 Schlieren, Switzerland -
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    06.06.2017
Published in:
  • Cell Reports. - 2017, vol. 19, no. 10, p. 1967–1976
English Alzheimer’s disease is characterized by intracerebral deposition of β-amyloid (Aβ). While Aβ40 is the most abundant form, neurotoxicity is mainly mediated by Aβ42. Sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases gives rise to full-length Aβ (Aβ1-x) and N-terminally truncated Aβ′ (Aβ11-x) whereas cleavage by α- and γ-secretases leads to the shorter p3 peptides (Aβ17-x). We uncovered significantly higher ratios of 42- versus 40-ending variants for Aβ and Aβ′ than for p3 secreted by mouse neurons and human induced pluripotent stem cell (iPSC)-derived neurons or produced in a cell-free γ-secretase assay with recombinant APP-CTFs. The 42:40 ratio was highest for Aβ′, followed by Aβ and then p3. Mass spectrometry analysis of APP intracellular domains revealed differential processing of APP-C83, APP-C89, and APP-C99 by γ-secretase already at the ε-cleavage stage. This mechanistic insight could aid in developing substrate-targeted modulators of APP-C99 processing to specifically lower the Aβ42:Aβ40 ratio without compromising γ-secretase function.
Faculty
Faculté des sciences et de médecine
Department
Département de Biologie
Language
  • English
Classification
Biological sciences
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/305974
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