Reducing ADAMTS-3 Inhibits Amyloid β Deposition in App Knock-in Mouse

Biol Pharm Bull. 2019;42(3):354-356. doi: 10.1248/bpb.b18-00899.


Reelin is a secreted protein that antagonizes the deposition and toxicity of amyloid β peptide (Aβ). Therefore, augmentation of Reelin activity may ameliorate Alzheimer's disease (AD). We have recently reported that a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS-3) cleaves and inactivates Reelin in the mouse brain. In the present study, we investigated the effect of reducing ADAMTS-3 on deposition of Aβ by crossbreeding drug-inducible ADAMTS-3 conditional knock-out (cKO) mice with "next-generation" AD model mice. We found that reducing ADAMTS-3 inhibited deposition of Aβ significantly in AppNL-F mice, which produce human wild-type Aβ. On the other hand, reducing ADAMTS-3 had no effect in AppNL-G-F mice, which produce the Arctic mutant Aβ (E22G) that forms protofibrils more efficiently than does wild-type Aβ. Thus, the findings suggest that the administration of an inhibitor against ADAMTS-3 will prevent the progression of AD pathology caused by deposition of wild-type Aβ.

Keywords: Alzheimer’s disease; Reelin; knock-in mouse; metalloprotease.

MeSH terms

  • ADAMTS Proteins / antagonists & inhibitors
  • ADAMTS Proteins / genetics
  • ADAMTS Proteins / metabolism*
  • Alzheimer Disease
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics*
  • Animals
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Disease Models, Animal
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Reelin Protein
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism


  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • Reelin Protein
  • RELN protein, human
  • Reln protein, mouse
  • Serine Endopeptidases
  • ADAMTS Proteins
  • Adamts3 protein, mouse