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

淀粉样β-肽是阿尔茨海默病(AD)患者老年斑的主要成分，由淀粉样前体蛋白(APP)在β-和γ-分泌酶作用下的蛋白水解酶降解而来。APP的α-裂解有可能阻止A-β的产生，因为它发生在A-β结构域中。我们报道了一种金属内肽酶，N-精氨酸二碱性转换酶(NRDC)，它能促进APP的α-裂解，从而在体外导致A-β的生成减少。为了阐明NRDC在AD中的体内作用，我们将在前脑表达NRDC的转基因小鼠与AD小鼠模型进行杂交。在这里，我们证明了神经元特异性的NRDC的过度表达阻止了AD小鼠模型中A-β的沉积。NRDC的过表达增强了小鼠脑内α-分泌酶的活性，而NRDC的缺失降低了小鼠脑内α-分泌酶的活性。我们的结果表明，NRDC通过调节α-分泌酶来控制A-β的形成。

Amyloid beta 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 beta- and gamma-secretases. Alpha-cleavage of APP has a potential to preclude the generation of A-beta because it occurs within the A-beta domain. We reported that a metalloendopeptidase, nardilysin (N-arginine dibasic convertase; NRDc) enhances alpha-cleavage of APP, which results in the decreased generation of A-beta 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-beta deposition in the AD mouse model. The activity of alpha-secretase in the mouse brain was enhanced by the overexpression of NRDc, and was reduced by the deletion of NRDc. Our results indicate that NRDc controls A-beta formation through the regulation of alpha-secretase.