Enhancement of alpha-secretase cleavage of amyloid precursor protein by a metalloendopeptidase nardilysin.
Amyloid-beta (Abeta) 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 beta- and gamma-secretases. Alternative cleavage of APP by alpha-secretase occurs within the Abeta domain and precludes generation of Abeta peptide. Three members of the ADAM (a disintegrin and metalloprotease) family of proteases, ADAM9, 10 and 17, are the main candidates for alpha-secretases. However, the mechanism that regulates alpha-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 alpha-secretase activity of ADAMs, which results in a decrease in the amount of Abeta generated. When expressed with ADAMs in cells, NRDc dramatically increased the secretion of alpha-secretase-cleaved soluble APP and reduced the amount of Abeta peptide generated. A peptide cleavage assay in vitro also showed that recombinant NRDc enhances ADAM17-induced cleavage of the peptide substrate corresponding to the alpha-secretase cleavage site of APP. A reduction of endogenous NRDc by RNA interference was accompanied by a decrease in the cleavage by alpha-secretase of APP and increase in the amount of Abeta 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 alpha-secretase activity of ADAMs, which may be a novel target for the treatment of Alzheimer's disease.
Hiraoka
Yoshinori
Y
Molecular Pathology Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, JapanBiomolecular Characterization Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Ohno
Mikiko
M
Molecular Pathology Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, JapanBiomolecular Characterization Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yoshida
Kazuhiro
K
Molecular Pathology Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, JapanBiomolecular Characterization Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Okawa
Katsuya
K
Molecular Pathology Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, JapanBiomolecular Characterization Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tomimoto
Hidekazu
H
Molecular Pathology Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, JapanBiomolecular Characterization Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kita
Toru
T
Molecular Pathology Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, JapanBiomolecular Characterization Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nishi
Eiichiro
E
Molecular Pathology Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, JapanBiomolecular Characterization Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
D051722:ADAM Proteins / Q000378:metabolism* / Q000494:pharmacology; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008666:Metalloendopeptidases / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D016296:Mutagenesis / Q000502:physiology; D009447:Neuroblastoma; D034622:RNA Interference / Q000502:physiology; D013379:Substrate Specificity; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; C087976:nardilysin; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse