The mechanism of thrombin deposition in Alzheimer's disease senile plaques and its pathological significance

阿尔茨海默病老年斑中凝血酶沉积机制及其病理意义

• 批准号: 05807056
• 负责人: AKIYAMA Haruhiko
• 金额: $ 1.28万
• 依托单位: Tokyo Institute of Psychiatry
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05807056/
• 关键词: thrombin; Alzheimer's disease; microglia; the blood coagulation system

Brain microglia and the complement system are activated in senile plaques.Tissue responses in Alzheimer's disease (AD) brain are similar to chronic inflammation in the peripheral organs.We hypothesize that such responses cause neuronal damage in AD brain.In the periphery, the blood coagulation system is activated at early stages of the inflammation.Thrombin is generated and plays important roles in the processes of the inflammation.Thrombin is a powerful chemoattractant of monocytes/macrophages.It causes the proliferation of fibroblasts. In AD brain, thrombin is deposited in senile plaques.In this study, I investigated the immunohistochemical localization of several components of the blood coagulation cascade such as tissue factor, factors VII,V and X in postmortem brain tissues of AD patients.The results suggested the activation of the extrinsic coagulation pathway.However, it has recently been suggested that a diverse types of cultured cells have a novel membrane-bound prothrombinase … More which generates thrombin in the absence of factor X.In addition, Mac-1, a membrane protein of macrophages and microglia, is known to activate factor X.Thus, multiple activation pathways may be involved in the activation of thrombin in brain.In this study, 6 antibodies were also raised in 12 rebbits against the functional thrombin receptor (TR).One of the antibodies stained senile plaques.Other antibodies, however, did not stain senile plaques and senile plaques and I could not confirm the specificity of the senile plaque staining by the first anti-TR antibody.Non of the anti-TR antibodies stained neuronal and glial cells, indicating that the expression of TR by these cells was below the sensitivity of the postmortem detection with immunohistochemistry.In in vitro studies, one antibody blocked the effect of thrombin to cultured cells and stained the cells.Expression of thrombomodulin (TM), another thrombin receptor, in brain was examined using commercially available antibodies.TM was found on vascular endothelial cells in postmortem brain tissue.The distribution of TM positive vessels was not related to the severity of AD lesions, however. Less

大脑小胶质细胞和补体系统在老年斑中被激活。阿尔茨海默病（AD）大脑中的组织反应与周围器官的慢性炎症相似。我们推测这种反应会导致AD大脑中的神经元损伤。在炎症的早期阶段，外周凝血系统被激活。凝血酶产生并在该过程中发挥重要作用 凝血酶是单核细胞/巨噬细胞的强大化学引诱剂。它会导致成纤维细胞增殖。在 AD 脑中，凝血酶沉积在老年斑中。在这项研究中，我研究了 AD 患者死后脑组织中凝血级联的几种成分（如组织因子、因子 VII、V 和 X）的免疫组织化学定位。结果表明外源性凝血途径被激活。然而，最近有人提出，多种类型的培养细胞具有新的功能。 膜结合凝血酶原酶在缺乏 X 因子的情况下会产生凝血酶。此外，已知巨噬细胞和小胶质细胞的膜蛋白 Mac-1 可以激活 X 因子。因此，大脑中凝血酶的激活可能涉及多种激活途径。在这项研究中，还在 12 个 rebbits 中产生了针对功能性凝血酶受体 (TR) 的 6 种抗体。其中一种抗体 然而，其他抗体没有对老年斑和老年斑进行染色，我无法证实第一种抗TR抗体对老年斑染色的特异性。抗TR抗体均未对神经元和神经胶质细胞进行染色，表明这些细胞的TR表达低于死后免疫组织化学检测的灵敏度。 体外研究中，一种抗体阻断了凝血酶对培养细胞的作用，并对细胞进行染色。使用市售抗体检查了大脑中另一种凝血酶受体血栓调节蛋白（TM）的表达。在死后脑组织的血管内皮细胞上发现了TM。然而，TM阳性血管的分布与AD病变的严重程度无关。较少的

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