Thrombin and prothrombin are expressed by neurons and glial cells and accumulate in neurofibrillary tangles in Alzheimer disease brain
Thrombin and prothrombin are expressed by neurons and glial cells and accumulate in neurofibrillary tangles in Alzheimer disease brain
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DOI：
10.1097/01.jnen.0000196133.74087.cb
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发表时间：
2006-01-01
影响因子：
3.2
通讯作者：
McGeer, PL
中科院分区：
文献类型：
--
作者：
Arai, T;Miklossy, J;McGeer, PL
凝血酶是一种丝氨酸蛋白酶，由其前体凝血酶原的蛋白水解裂解产生。我们之前的研究表明凝血酶蛋白可水解微管相关蛋白tau，而tau蛋白的磷酸化可抑制这一过程。为了进一步表征凝血酶在大脑中的作用，我们研究了凝血酶原和凝血酶在培养的脑细胞和凝血酶在对照组、阿尔茨海默病（AD）和关岛帕金森-痴呆复合体（PDCG）大脑中的表达。我们通过逆转录聚合酶链反应表明凝血酶原mRNA在脑组织中表达。神经母细胞瘤细胞、培养的人类星形胶质细胞、少突胶质细胞和小胶质细胞。我们还通过免疫组织化学证明凝血酶原和凝血酶原蛋白存在于大脑中，并对这两种蛋白使用特异性单克隆和多克隆抗体。所有抗体均可染色血管、正常锥体神经元及其突起和部分星形胶质细胞的残留血清。此外，在AD和PDCG病例中，所有抗体都能染色细胞外和细胞内神经原纤维缠结（nft）、老年斑和反应性小胶质细胞。凝血酶原和凝血酶在脑细胞中的普遍表达表明凝血酶在正常大脑中起着重要的生理作用。凝血酶和凝血酶原在nft中的积累支持了凝血酶可能参与tau蛋白水解的假设，而tau代谢失败可能导致其在神经退行性疾病中的聚集。
Thrombin is a serine protease that is generated by proteolytic cleavage of its precursor, prothrombin. We previously showed that thrombin proteolyses the microtubule-associated protein tau and that phosphorylation of tau inhibits this process. To characterize further the role of thrombin in the brain, we investigated prothrombin and thrombin expression in cultured brain cells and in brains of control, Alzheimer disease (AD) and parkinsonism-dementia complex of Guam (PDCG). We show by reverse transcriptase-polymerase chain reaction that prothrombin mRNA is expressed in brain tissues,. neuroblastoma cells, and cultured human astrocytes, oligodendrocytes, and microglial cells. We also show by immunohistochemistry that the proteins prothrombin and thrombin are present in brain using specific monoclonal and polyclonal antibodies for both proteins. All antibodies stained residual serum in blood vessels, as well as normal pyramidal neurons and their processes, and some astrocytes. Additionally, in AD and PDCG cases, all antibodies stained extra- and intracellular neurofibrillary tangles (NFTs), senile plaques, and reactive microglial cells. The ubiquitous expression of prothrombin and thrombin in brain cells suggests that thrombin plays an important physiological role in normal brain. The accumulation of thrombin and prothrombin in NFTs supports the hypothesis that thrombin may be involved in tau proteolysis and that failure to metabolize tau may lead to its aggregation in neurodegenerative diseases.