Iwata Nobuhisa, Higuchi Makoto, Saido Takaomi C
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan.
Pharmacol Ther. 2005 Nov;108(2):129-48. doi: 10.1016/j.pharmthera.2005.03.010. Epub 2005 Aug 19.
The accumulation of amyloid-beta peptide (Abeta), a physiological peptide, in the brain is a triggering event leading to the pathological cascade of Alzheimer's disease (AD) and appears to be caused by an increase in the anabolic activity, as seen in familial AD cases or by a decrease in catabolic activity. Neprilysin is a rate-limiting peptidase involved in the physiological degradation of Abeta in the brain. As demonstrated by reverse genetics studies, disruption of the neprilysin gene causes elevation of endogenous Abeta levels in mouse brain in a gene-dose-dependent manner. Thus, the reduction of neprilysin activity will contribute to Abeta accumulation and consequently to AD development. Evidence that neprilysin in the hippocampus and cerebral cortex is down-regulated with aging and from an early stage of AD development supports a close association of neprilysin with the etiology and pathogenesis of AD. Therefore, the up-regulation of neprilysin represents a promising strategy for therapy and prevention. Recently, somatostatin, which acts via a G-protein-coupled receptor (GPCR), has been identified as a modulator that increases brain neprilysin activity, resulting in a decrease of Abeta levels. Thus, it may be possible to pharmacologically control brain Abeta levels with somatostatin receptor agonists.
淀粉样β肽（Aβ）是一种生理性肽，其在大脑中的积累是引发阿尔茨海默病（AD）病理级联反应的事件，似乎是由合成代谢活性增加引起的，如在家族性AD病例中所见，或者是由分解代谢活性降低引起的。中性内肽酶是参与大脑中Aβ生理性降解的限速肽酶。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大脑中内源性Aβ水平升高。因此，中性内肽酶活性的降低将导致Aβ积累，进而导致AD的发展。海马体和大脑皮质中的中性内肽酶随着衰老以及从AD发展的早期阶段就被下调，这一证据支持了中性内肽酶与AD的病因和发病机制密切相关。因此，上调中性内肽酶是一种有前景的治疗和预防策略。最近，通过G蛋白偶联受体（GPCR）起作用的生长抑素已被确定为一种调节剂，可增加大脑中性内肽酶活性，从而降低Aβ水平。因此，有可能用生长抑素受体激动剂从药理学上控制大脑Aβ水平。
