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PNAS:美科學家發現診斷老年癡呆癥新標記

發布時間:2018-06-07 950 次瀏覽

近日,美國國家科學院院刊(PNAS)在線發表了美國洛克菲勒大學研究人員關于阿爾茨海默病的最新研究進展。

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近日,美國國家科學院院刊(PNAS)在線發表了美國洛克菲勒大學研究人員關于阿爾茨海默病的最新研究進展。

阿爾茨海默病(AD)俗稱老年癡呆,是一種由于β淀粉樣肽(Aβ)在神經元中積累導致的神經退行性病變,在該疾病的發病過程中可能受到多種分子機制的影響。越來越多的證據表明AD病變伴隨炎癥發生,但炎癥的來源仍不清楚。研究人員對循環系統中的Aβ是否能夠通過血漿接觸激活系統(plasma contact activation system)誘發AD相關性炎癥進行了研究。

血漿接觸激活系統是一種蛋白水解級聯反應,研究人員發現這種蛋白水解級聯反應是通過血漿蛋白因子XII(FXII)的激活進行觸發的,并會導致激肽釋放酶血管舒緩素介導的對高分子量激肽原(HK)的切割,釋放具有炎癥促進作用的血管舒緩激肽。體外實驗證明Aβ能夠促進FXII依賴性的HK切割,除此之外,切割后的HK增加也出現在AD病人的腦脊髓液中。在該研究中,研究人員發現在AD病人的血漿中FXII激活,激肽釋放酶血管舒緩素活性和激肽原的切割均出現增加,而在AD小鼠模型和Aβ42處理的野生型小鼠血漿中也可觀察到血漿接觸激活系統活性增加。

這些結果表明Aβ42介導的接觸激活系統可發生在AD病人血漿中,對于阿爾茨海默病的診斷和治療均有重要提示作用。

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

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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