长期达比加群治疗延缓TgCRND8小鼠模型中阿尔茨海默病的发病

BACKGROUND 阿尔茨海默氏病（AD）是一种多因素神经退行性疾病，具有重要的血管和止血变化，在诊断和治疗期间应予以考虑。

OBJECTIVES 这项研究评估了达比加群（一种临床认可的口服直接凝血酶抑制剂，具有低脑出血风险）的抗凝作用是否能改善AD转基因小鼠模型的AD发病机理。

METHODS 用达比加群酯或安慰剂治疗TgCRND8 AD小鼠及其野生型同窝动物1年。使用Barnes迷宫评估认知度，并通过动脉旋转标记检查脑灌注。在分子水平上，进行了蛋白质印迹和组织化学分析，以分析纤维蛋白含量，淀粉样蛋白负荷，神经炎症活性和血脑屏障（BBB）完整性。

RESULTS 达比加群抗凝可预防AD小鼠大脑中的记忆力下降，脑灌注不足和有毒纤维蛋白沉积。此外，长期达比加群治疗显着降低了淀粉样斑块，寡聚体，吞噬小胶质细胞和浸润的T细胞的程度，分别降低了23.7％，51.8％，31.3％和32.2％。达比加群抗凝治疗还预防了AD相关的星形胶质细胞变性和周细胞改变，并在BBB的星形细胞周血管末端维持了水通道aquaporin-4的表达。

CONCLUSIONS 达比加群的长期抗凝作用可抑制凝血酶和在AD中形成闭塞性血栓;保持认知，脑灌注和血脑屏障功能；改善了AD小鼠的神经炎症和淀粉样蛋白沉积。我们的结果为直接口服抗凝剂的使用在AD中是否具有治疗价值开辟了一个未来的研究领域。

Long-Term Dabigatran Treatment Delays Alzheimer's Disease Pathogenesis in the TgCRND8 Mouse Model.

Cortes-Canteli M,et al  J Am Coll Cardiol             2019  Oct 15MORE            

Abstract           翻译      

BACKGROUND Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with important vascular and hemostatic alterations that should be taken into account during diagnosis and treatment.OBJECTIVES This study evaluates whether anticoagulation with dabigatran, a clinically approved oral direct thrombin inhibitor with a low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in a transgenic mouse model of AD.METHODS TgCRND8 AD mice and their wild-type littermates were treated for 1 year with dabigatran etexilate or placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling. At the molecular level, Western blot and histochemical analyses were performed to analyze fibrin content, amyloid burden, neuroinflammatory activity, and blood-brain barrier (BBB) integrity.RESULTS Anticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells by 23.7%, 51.8%, 31.3%, and 32.2%, respectively. Dabigatran anticoagulation also prevented AD-related astrogliosis and pericyte alterations, and maintained expression of the water channel aquaporin-4 at astrocytic perivascular endfeet of the BBB.CONCLUSIONS Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD.