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

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）大脑的组织反应与周围器官的慢性炎症相似。我们假设这些反应会导致AD大脑的神经元损伤。在外周，凝血系统在炎症的早期阶段被激活。凝血酶的产生在炎症过程中起重要作用。凝血酶是一种强大的单核/巨噬细胞的化学引诱剂。它会引起成纤维细胞的增殖。在AD大脑中，凝血酶沉积在老年斑中。在本研究中，我研究了AD患者死后脑组织中组织因子、因子VII、因子V、因子X等血凝级联中几种组分的免疫组织化学定位。结果提示外源性凝血途径被激活。然而，最近有研究表明，多种类型的培养细胞具有一种新的膜结合凝血酶原…More，它在缺乏x因子的情况下产生凝血酶。此外，巨噬细胞和小胶质细胞的膜蛋白Mac-1已知可激活x因子，因此，脑凝血酶的激活可能涉及多种激活途径。在本研究中，在12个条带中也有6个针对功能性凝血酶受体（TR）的抗体。其中一种抗体染色老年斑。而其他抗体不能对老年斑和老年斑进行染色，我无法确认第一抗tr抗体对老年斑染色的特异性。没有抗TR抗体染色神经元和神经胶质细胞，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。在体外研究中，一种抗体阻断凝血酶对培养细胞的作用并使细胞染色。用市售抗体检测脑内另一凝血酶受体血栓调节蛋白（TM）的表达。在死后脑组织血管内皮细胞上发现TM。然而，TM阳性血管的分布与AD病变的严重程度无关。少

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