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PNAS:美科学家发现诊断老年痴呆症新标记

2015-05-19 17:36  
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PNAS:美科学家发现诊断老年痴呆症新标记

近日,美国国家科学院院刊(PNAS)在线发表了美国洛克菲勒大学研究人员关于阿尔茨海默病的最新研究进展。

阿尔茨海默病(AD)俗称老年痴呆,是一种由于β淀粉样肽(Aβ)在神经元中积累导致的神经退行性病变,在该疾病的发病过程中可能受到多种分子机制的影响。越来越多的证据表明AD病变伴随炎症发生,但炎症的来源仍不清楚。研究人员对循环系统中的Aβ是否能够通过血浆接触激活系统(plasma contact activation system)诱发AD相关性炎症进行了研究。

血浆接触激活系统是一种蛋白水解级联反应,研究人员发现这种蛋白水解级联反应是通过血浆蛋白因子XII(FXII)的激活进行触发的,并会导致激肽释放酶血管舒缓素介导的对高分子量激肽原(HK)的切割,释放具有炎症促进作用的血管舒缓激肽。体外实验证明Aβ能够促进FXII依赖性的HK切割,除此之外,切割后的HK增加也出现在AD病人的脑脊髓液中。在该研究中,研究人员发现在AD病人的血浆中FXII激活,激肽释放酶血管舒缓素活性和激肽原的切割均出现增加,而在AD小鼠模型和Aβ42处理的野生型小鼠血浆中也可观察到血浆接触激活系统活性增加。

这些结果表明Aβ42介导的接触激活系统可发生在AD病人血浆中,对于阿尔茨海默病的诊断和治疗均有重要提示作用。

Activation of the factor XII-driven contact system in Alzheimer’s disease patient and mouse model plasma

  1. Sidney Stricklanda,1
  1. Edited by Gregory A. Petsko, Weill Cornell Medical College, New York, NY, and approved February 18, 2015 (received for review December 11, 2014)

Alzheimer’s disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which likely contributes to disease via multiple mechanisms. Increasing evidence implicates inflammation in AD, the origins of which are not completely understood. We investigated whether circulating Aβ could initiate inflammation in AD via the plasma contact activation system. This proteolytic cascade is triggered by the activation of the plasma protein factor XII (FXII) and leads to kallikrein-mediated cleavage of high molecular-weight kininogen (HK) and release of proinflammatory bradykinin. Aβ has been shown to promote FXII-dependent cleavage of HK in vitro. In addition, increased cleavage of HK has been found in the cerebrospinal fluid of patients with AD. Here, we show increased activation of FXII, kallikrein activity, and HK cleavage in AD patient plasma. Increased contact system activation is also observed in AD mouse model plasma and in plasma from wild-type mice i.v. injected with Aβ42. Our results demonstrate that Aβ42-mediated contact system activation can occur in the AD circulation and suggest new pathogenic mechanisms, diagnostic tests, and therapies for AD.

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