Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid-beta precursor protein cleavage

Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2548-53. doi: 10.1073/pnas.0308655100.


Amyloid-beta precursor protein (APP), a type I membrane protein, is physiologically processed by alpha- or beta-secretases that cleave APP N-terminal to the transmembrane region. Extracellular alpha-/beta-cleavage of APP generates a large secreted N-terminal fragment, and a smaller cellular C-terminal fragment. Subsequent gamma-secretase cleavage in the transmembrane region of the C-terminal fragment induces secretion of small extracellular peptides, including Abeta40 and Abeta42, which are instrumental in the pathogenesis of Alzheimer's disease, and intracellular release of a cytoplasmic tail fragment. Although APP resembles a cell-surface receptor, no functionally active extracellular ligand for APP that might regulate its proteolytic processing has been described. We now show that F-spondin, a secreted signaling molecule implicated in neuronal development and repair, binds to the conserved central extracellular domain of APP and inhibits beta-secretase cleavage of APP. Our data indicate that F-spondin may be an endogenous regulator of APP cleavage, and suggest that the extracellular domains of APP are potential drug targets for interfering with beta-secretase cleavage.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / isolation & purification
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Brain / metabolism
  • Cell Line
  • Chromatography, Affinity
  • Extracellular Matrix Proteins
  • Humans
  • Hydrolysis
  • Intercellular Signaling Peptides and Proteins
  • Kinetics
  • Ligands
  • Peptides / genetics
  • Peptides / isolation & purification
  • Peptides / metabolism*
  • Rats
  • Recombinant Fusion Proteins / isolation & purification
  • Recombinant Fusion Proteins / metabolism
  • Transfection


  • Amyloid beta-Protein Precursor
  • Extracellular Matrix Proteins
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Peptides
  • Recombinant Fusion Proteins
  • SPON1 protein, human
  • Spon1 protein, rat