Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice
Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice
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DOI：
10.1182/blood-2016-11-753202
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发表时间：
2017-05-04
期刊：
影响因子：
20.3
通讯作者：
Strickland, Sidney
中科院分区：
文献类型：
--
作者：
Chen, Zu-Lin;Revenko, Alexey S.;Strickland, Sidney
在许多阿尔茨海默病（AD）患者中发现血管异常和炎症，但这些变化是否在AD中起致病作用尚不清楚。因子XII （FXII）启动的接触系统可触发血管病理和炎症，并在AD患者和AD小鼠中被激活。我们研究了接触系统在AD发病机制中的作用。在AD小鼠模型中，高分子量激肽原（HK）的切割增加，这是接触系统炎症臂激活的标志，并且这种切割与脑炎症的发生在时间上相关。在AD小鼠中，FXII的缺失抑制了血浆中HK的切割，减少了神经炎症、纤维蛋白原沉积和大脑中的神经变性。此外，fxii缺失的AD小鼠比未治疗的AD小鼠表现出更好的认知功能。这些结果表明fxii介导的接触系统激活参与了AD的发病机制，因此该系统可能为AD的治疗提供新的靶点。
Vascular abnormalities and inflammation are found in many Alzheimer disease (AD) patients, but whether these changes play a causative role in AD is not clear. The factor XII (FXII)-initiated contact system can trigger both vascular pathology and inflammation and is activated in AD patients and AD mice. We have investigated the role of the contact system in AD pathogenesis. Cleavage of high-molecular-weight kininogen (HK), a marker for activation of the inflammatory arm of the contact system, is increased in a mouse model of AD, and this cleavage is temporally correlated with the onset of brain inflammation. Depletion of FXII in AD mice inhibited HK cleavage in plasma and reduced neuroinflammation, fibrinogen deposition, and neurodegeneration in the brain. Moreover, FXII-depleted AD mice showed better cognitive function than untreated AD mice. These results indicate that FXII-mediated contact system activation contributes to AD pathogenesis, and therefore this system may offer novel targets for AD treatment.