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Keywords:

  • a disintegrin and metalloprotease proteases;
  • α-secretase;
  • Alzheimer’s disease;
  • amyloid-β;
  • ectodomain shedding;
  • nardilysin

Abstract

Amyloid-β (Aβ) peptide, the principal component of senile plaques in the brains of patients with Alzheimer’s disease, is derived from proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Alternative cleavage of APP by α-secretase occurs within the Aβ domain and precludes generation of Aβ peptide. Three members of the ADAM (a disintegrin and metalloprotease) family of proteases, ADAM9, 10 and 17, are the main candidates for α-secretases. However, the mechanism that regulates α-secretase activity remains unclear. We have recently demonstrated that nardilysin (EC 3.4.24.61, N-arginine dibasic convertase; NRDc) enhances ectodomain shedding of heparin-binding epidermal growth factor-like growth factor through activation of ADAM17. In this study, we show that NRDc enhances the α-secretase activity of ADAMs, which results in a decrease in the amount of Aβ generated. When expressed with ADAMs in cells, NRDc dramatically increased the secretion of α-secretase-cleaved soluble APP and reduced the amount of Aβ peptide generated. A peptide cleavage assay in vitro also showed that recombinant NRDc enhances ADAM17-induced cleavage of the peptide substrate corresponding to the α-secretase cleavage site of APP. A reduction of endogenous NRDc by RNA interference was accompanied by a decrease in the cleavage by α-secretase of APP and increase in the amount of Aβ generated. Notably, NRDc is clearly expressed in cortical neurons in human brain. Our results indicate that NRDc is involved in the metabolism of APP through regulation of the α-secretase activity of ADAMs, which may be a novel target for the treatment of Alzheimer’s disease.