Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ-secretase modulators

Dieter Petit, Manuel Hitzenberger, Sam Lismont, Katarzyna Marta Zoltowska, Natalie S. Ryan, Marc Mercken, François Bischoff, Martin Zacharias, Lucía Chávez-Gutiérrez

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

γ-Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Presenilin Enhancer 2 (PEN-2), and Anterior Pharynx Defective 1 (APH1) are the essential subunits of GSECs. Mutations in PSEN and the Amyloid Precursor Protein (APP) cause early-onset AD. GSECs successively cut APP to generate amyloid-β (Aβ) peptides of various lengths. AD-causing mutations destabilize GSEC-APP/Aβn interactions and thus enhance the production of longer Aβs, which elicit neurotoxic events underlying pathogenesis. Here, we investigated the molecular strategies that anchor GSEC and APP/Aβn during the sequential proteolysis. Our studies reveal that a direct interaction between NCT ectodomain and APPC99 influences the stability of GSEC-Aβn assemblies and thereby modulates Aβ length. The data suggest a potential link between single-nucleotide variants in NCSTN and AD risk. Furthermore, our work indicates that an extracellular interface between the protease (NCT, PSEN) and the substrate (APP) represents the target for compounds (GSMs) modulating Aβ length. Our findings may guide future rationale-based drug discovery efforts.

Original languageEnglish
Article numbere101494
JournalEMBO Journal
Volume38
Issue number12
DOIs
StatePublished - 17 Jun 2019
Externally publishedYes

Keywords

  • Alzheimer's disease
  • amyloid-beta
  • Nicastrin
  • γ-secretase
  • γ-secretase modulators

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