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

Cell. 2017 Jul 27;170(3):443-456.e14. doi: 10.1016/j.cell.2017.07.004.


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.

Keywords: Alzheimer’s disease; amyloid beta; amyloid precursor protein; enzyme thermoactivity; presenilin; protein thermosability; γ-secretase.

MeSH terms

  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / genetics*
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Cell Line
  • Endopeptidases
  • Enzyme Stability
  • Female
  • HEK293 Cells
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Models, Molecular
  • Mutation
  • Peptide Hydrolases / chemistry
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism*
  • Presenilin-1 / chemistry
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism*


  • Amyloid beta-Protein Precursor
  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • APH1A protein, human
  • Endopeptidases
  • Peptide Hydrolases