A metalloproteinase inhibitor domain in Alzheimer amyloid protein precursor

Nature. 1993 Apr 29;362(6423):839-41. doi: 10.1038/362839a0.


Extracellular deposition of amyloid beta-protein (beta-AP), or A4 protein (M(r) 4,000), is associated with Alzheimer's disease and with Down's syndrome (trisomy for chromosome 21). The large membrane-bound precursor protein (APP) of beta-AP is normally cleaved within the beta-AP region by a putative proteinase (APP secretase) to release its extracellular portion; beta-AP is produced by an alternative proteolytic processing. Here we demonstrate that APP contains a proteinase inhibitor domain for the matrix metalloproteinase gelatinase A, which is located in the C-terminal glycosylated region of the secretory forms of APP. In addition, we show that the gelatinase has an APP secretase-like activity, which hydrolyses the Lys16-Leu17 bond in the beta-AP sequence. Our results indicate that the proteinase inhibitor domain of APP and gelatinase A may be involved in the formation of beta-AP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / metabolism*
  • Aspartic Acid Endopeptidases
  • Endopeptidases / metabolism
  • Glycoproteins / chemistry
  • Glycoproteins / metabolism
  • Humans
  • Hydrolysis
  • Matrix Metalloproteinase 2
  • Metalloendopeptidases / antagonists & inhibitors*
  • Molecular Sequence Data
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Tissue Inhibitor of Metalloproteinase-2
  • Tissue Inhibitor of Metalloproteinases
  • Tumor Cells, Cultured


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Glycoproteins
  • Neoplasm Proteins
  • Peptide Fragments
  • Tissue Inhibitor of Metalloproteinases
  • Tissue Inhibitor of Metalloproteinase-2
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2