Iwata Nobuhisa, Saido Takaomi C
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Nihon Yakurigaku Zasshi. 2003 Jul;122(1):5-14. doi: 10.1254/fpj.122.5.
The deposition of amyloid-beta peptide (Abeta) causes the long-term pathological cascade of Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in Abeta degradation in brain. As demonstrated by reverse genetics, the disruption of neprilysin gene causes an elevation in endogenous Abeta levels in the mouse brain in a gene-dose-dependent manner. Therefore, a reduction of neprilysin activity will contribute to Abeta deposition and thus to AD development. Neprilysin is localized at presynapses and on axons, and its expression levels are decreased at the terminal zones and on axons of the lateral perforant pathway and the mossy fibers with aging in mice, suggesting that local concentrations of Abeta are likely to be elevated at the sites, which play crucial roles on certain forms of learning and memory and are highly vulnerable to AD. Overexpression of neprilysin decreased both extracellular and intracellular Abeta levels in primary cortical neurons. These results indicate that up-regulation of neprilysin activity would be a relevant strategy for therapy and prevention through reduction of the Abeta levels. Recently, we have found that a certain neuropeptide regulates the expression of neprilysin in primary neurons. Since a number of receptors for neuropeptides are G-protein-coupled receptors, we would control brain Abetalevels pharmacologically by the manipulation of neprilysin activity.
β-淀粉样肽（Aβ）的沉积引发了阿尔茨海默病（AD）的长期病理级联反应。中性内肽酶是一种限速肽酶，参与大脑中Aβ的降解。反向遗传学研究表明，中性内肽酶基因的破坏会以基因剂量依赖的方式导致小鼠脑内内源性Aβ水平升高。因此，中性内肽酶活性的降低将导致Aβ沉积，进而促进AD的发展。中性内肽酶定位于突触前和轴突，在小鼠中，随着年龄增长，其在侧穿通通路和苔藓纤维的终末区及轴突上的表达水平降低，这表明这些部位的Aβ局部浓度可能升高，而这些部位在某些形式的学习和记忆中起关键作用，且对AD高度敏感。在原代皮层神经元中，中性内肽酶的过表达降低了细胞外和细胞内的Aβ水平。这些结果表明，通过降低Aβ水平，上调中性内肽酶活性将是一种相关的治疗和预防策略。最近，我们发现某种神经肽可调节原代神经元中中性内肽酶的表达。由于许多神经肽受体是G蛋白偶联受体，我们可以通过操纵中性内肽酶活性从药理学角度控制脑内Aβ水平。
