Saito Takashi, Takaki Yoshie, Iwata Nobuhisa, Trojanowski John, Saido Takaomi C
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Sci Aging Knowledge Environ. 2003 Jan 22;2003(3):PE1. doi: 10.1126/sageke.2003.3.pe1.
Amyloid-beta peptide (Abeta), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We have focused our attention and effort on elucidating the unresolved aspect of Abeta metabolism: proteolytic degradation. Among a number of Abeta-degrading enzyme candidates, we used a novel in vivo paradigm to identify a member of the neutral endopeptidase family, neprilysin, as the major Abeta catabolic enzyme. Neprilysin deficiency results in defects in the metabolism of endogenous Abeta 40 and 42 in a gene dose-dependent manner. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Abeta accumulation. Moreover, we discuss the fact that an aging-dependent decline of neprilysin activity, which leads to elevation of Abeta concentrations in the brain, is a natural process that precedes AD pathology. In this Perspective, we hypothesize that neprilysin down-regulation has a role in sporadic AD (SAD) pathogenesis, and we propose that this knowledge be used for developing preventive and therapeutic strategies through use of a G protein-coupled receptor (GPCR).
β-淀粉样肽（Aβ）是阿尔茨海默病（AD）的致病因子，是大脑中的一种生理代谢产物。我们一直致力于阐明Aβ代谢中尚未解决的方面：蛋白水解降解。在众多Aβ降解酶候选物中，我们采用了一种新的体内模型来鉴定中性内肽酶家族的一个成员，即中性内肽酶，它是主要的Aβ分解代谢酶。中性内肽酶缺乏会以基因剂量依赖的方式导致内源性Aβ40和Aβ42代谢缺陷。我们的观察结果表明，即使是由衰老引起的中性内肽酶活性的部分下调，也可能通过促进Aβ积累而导致AD的发展。此外，我们讨论了这样一个事实，即中性内肽酶活性随年龄增长而下降，导致大脑中Aβ浓度升高，这是AD病理发生之前的一个自然过程。在本观点中，我们假设中性内肽酶下调在散发性AD（SAD）发病机制中起作用，并建议利用这一知识通过使用G蛋白偶联受体（GPCR）来制定预防和治疗策略。
