|Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1995: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1994: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1993: ¥800,000 (Direct Cost: ¥800,000)
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
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