title: Nardilysin prevents amyloid plaque formation by enhancing α-secretase activity in an Alzheimer's disease mouse model.
abstract: Amyloid beta (Aβ) peptide, the main component of senile plaques in patients with Alzheimer's disease (AD), is derived from proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Alpha-cleavage of APP by α-secretase has a potential to preclude the generation of Aβ because it occurs within the Aβ domain. We previously reported that a metalloendopeptidase, nardilysin (N-arginine dibasic convertase; NRDc) enhances α-cleavage of APP, which results in the decreased generation of Aβ in vitro. To clarify the in vivo role of NRDc in AD, we intercrossed transgenic mice expressing NRDc in the forebrain with an AD mouse model. Here we demonstrate that the neuron-specific overexpression of NRDc prevents Aβ deposition in the AD mouse model. The activity of α-secretase in the mouse brain was enhanced by the overexpression of NRDc, and was reduced by the deletion of NRDc. However, reactive gliosis adjacent to the Aβ plaques, one of the pathological features of AD, was not affected by the overexpression of NRDc. Taken together, our results indicate that NRDc controls Aβ formation through the regulation of α-secretase.
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Mikiko
authors: M
authors: Ohno
authors: Yoshinori
authors: Y
authors: Hiraoka
authors: Stefan F
authors: SF
authors: Lichtenthaler
authors: Kiyoto
authors: K
authors: Nishi
authors: Sayaka
authors: S
authors: Saijo
authors: Tatsuhiko
authors: T
authors: Matsuoka
authors: Hidekazu
authors: H
authors: Tomimoto
authors: Wataru
authors: W
authors: Araki
authors: Ryosuke
authors: R
authors: Takahashi
authors: Toru
authors: T
authors: Kita
authors: Takeshi
authors: T
authors: Kimura
authors: Eiichiro
authors: E
authors: Nishi
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism*; D059748:Proteolysis
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D008666:Metalloendopeptidases; C087976:nardilysin
keywords: Alzheimer's disease; Amyloid precursor protein; Metalloendopeptidase; Nardilysin; α-secretase