Peptides based on the presenilin-APP binding domain inhibit APP processing and Aβ production through interfering with the APP transmembrane domain

FASEB J. 2012 Sep;26(9):3765-78. doi: 10.1096/fj.11-201368. Epub 2012 Jun 1.


Presenilins (PSENs) form the catalytic component of the γ-secretase complex, responsible for intramembrane proteolysis of amyloid precursor protein (APP) and Notch, among many other membrane proteins. Previously, we identified a PSEN1-binding domain in APP, encompassing half of the transmembrane domain following the amyloid β (Aβ) sequence. Based on this, we designed peptides mimicking this interaction domain with the aim to selectively block APP processing and Aβ generation through interfering with enzyme-substrate binding. We identified a peptide sequence that, when fused to a virally derived translocation peptide, significantly lowered Aβ production (IC(50): 317 nM) in cell-free and cell-based assays using APP-carboxy terminal fragment as a direct γ-secretase substrate. Being derived from the APP sequence, this inhibitory peptide did not affect NotchΔE γ-cleavage, illustrating specificity and potential therapeutic value. In cell-based assays, the peptide strongly suppressed APP shedding, demonstrating that it exerts the inhibitory effect already upstream of γ-secretase, most likely through steric hindrance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / biosynthesis*
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Proteins / metabolism*
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Peptides / metabolism*
  • Presenilins / metabolism*
  • Protein Processing, Post-Translational*
  • Surface Plasmon Resonance


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Membrane Proteins
  • Peptides
  • Presenilins