Nardilysin prevents amyloid plaque formation by enhancing ¦Á-secretase activity in an Alzheimer's disease mouse model

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• 作者：Mikiko Ohno ; Yoshinori Hiraoka ; Stefan F. Lichtenthaler ; Kiyoto Nishi ; Sayaka Saijo ; Tatsuhiko Matsuoka ; Hidekazu Tomimoto ; Wataru Araki ; Ryosuke Takahashi ; Toru Kita ; Takeshi Kimura ; Eiichiro Nishi
• 关键词：¦Á-secretase ; Metalloendopeptidase ; Nardilysin ; Amyloid precursor protein ; Alzheimer's disease
• 刊名：Neurobiology of Aging
• 出版年：2014
• 出版时间：January, 2014
• 年：2014
• 卷：35
• 期：1
• 页码：213-222
• 全文大小：2083 K

文摘

Amyloid beta (A¦Â) 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 ¦Â- and ¦Ã-secretases. Alpha-cleavage of APP by ¦Á-secretase has a potential to preclude the generation of A¦Â because it occurs within the A¦Â domain. We previously reported that a metalloendopeptidase, nardilysin (N-arginine dibasic convertase; NRDc) enhances ¦Á-cleavage of APP, which results in the decreased generation of A¦Â 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 A¦Â deposition in the AD mouse model. The activity of ¦Á-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 A¦Â plaques, one of the pathological features of AD, was not affected by the overexpression of NRDc. Taken together, our results indicate that NRDc controls A¦Â formation through the regulation of ¦Á-secretase.