Mouri Akihiro, Zou Li-Bo, Iwata Nobuhisa, Saido Takaomi C, Wang Dayong, Wang Min-Wei, Noda Yukihiro, Nabeshima Toshitaka
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
Behav Brain Res. 2006 Mar 15;168(1):83-91. doi: 10.1016/j.bbr.2005.10.014. Epub 2005 Dec 19.
An accumulation of amyloid beta peptide (Abeta) due to an imbalance between anabolism and catabolism triggers Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in the catabolism of Abeta in brain. We investigated whether rats continuously infused with thiorphan, a specific inhibitor for neprilysin, into the cerebral ventricle cause cognitive dysfunction, with an accumulation of Abeta in the brain. Thiorphan-infused rats displayed significant cognitive dysfunction in the ability to discriminate in the object recognition test and spatial memory in the water maze test, but not in other hippocampus-dependent learning and memory tasks. Thiorphan infusion also elevated the Abeta40 level in the insoluble fraction of the cerebral cortex, but not that of the hippocampus. There was no significant difference in the nicotine-stimulated release of acetylcholine in the hippocampus between vehicle- and thiorphan-infused rats. These results indicate that continuous infusion of thiorphan into the cerebral ventricle causes cognitive dysfunction by raising the level of Abeta in the cerebral cortex, and suggest that a reduction of neprilysin activity contribute to the deposition of Abeta and development of AD.
由于合成代谢与分解代谢失衡导致的β淀粉样肽（Aβ）积累引发阿尔茨海默病（AD）。中性内肽酶是一种限速肽酶，参与大脑中Aβ的分解代谢。我们研究了持续向脑室注射硫磷酰胺（一种中性内肽酶的特异性抑制剂）的大鼠是否会因大脑中Aβ的积累而导致认知功能障碍。注射硫磷酰胺的大鼠在物体识别测试中的辨别能力和水迷宫测试中的空间记忆方面表现出显著的认知功能障碍，但在其他依赖海马体的学习和记忆任务中则没有。注射硫磷酰胺还会提高大脑皮质不溶性部分的Aβ40水平，但不会提高海马体的Aβ40水平。在注射溶剂和注射硫磷酰胺的大鼠之间，海马体中尼古丁刺激的乙酰胆碱释放没有显著差异。这些结果表明，持续向脑室注射硫磷酰胺会通过提高大脑皮质中的Aβ水平导致认知功能障碍，并表明中性内肽酶活性的降低有助于Aβ的沉积和AD的发展。
