纤维蛋白通过诱导tau蛋白聚集介导卒中后认知功能障碍的机制研究

认知功能障碍是缺血性脑卒中最重要的后遗症之一，其发病机制不清，也缺乏有效的治疗措施。近期研究发现神经元内Tau蛋白的病理性聚集在卒中后认知功能障碍的发生中起到重要作用。纤维蛋白是一种重要的凝血因子，可自身聚集形成聚集体参与凝血过程。纤维蛋白的聚集过程与Tau的聚集过程相似。我们的前期研究发现脑梗死后局部增高的溶血磷脂酸（LPA）导致血脑屏障损伤，使纤维蛋白通过受损的血脑屏障渗入脑实质，体外实验发现纤维蛋白可促进神经元内Tau的聚集。据此我们提出：脑卒后血管内的纤维蛋白通过受损的血脑屏障渗入脑实质，诱导神经元内Tau的异常聚集，导致卒中后认知功能障碍的发生。本研究中我们将使用Tau转基因小鼠及Tau基因敲除小鼠，联合运用分子生物学、细胞生物学、动物行为学和组织形态学等方法，阐明纤维蛋白诱导Tau的病理性聚集，参与卒中后认知功能障碍发病的分子机制，为卒中后认知功能障碍的防治提供新的靶点。

Cognitive impairment is one of the most important sequelae of ischemic stroke. The pathogenesis of post-stroke cognitive impairment remains unclear. Recently, it was demonstrated that the aggregation of Tau in neurons contributes to the onset of post-stroke cognitive impairment. Fibrin is an important coagulation factor, which can form fibrillar aggregates. Its aggregation process is similar to that of Tau. Our previous experiments found that the concentration of lysophosphatidic acid (LPA) was increased in the ischemic brain tissue, and induces increased blood-brain barrier permeability, through which the fibrin can enter the brain parenchyma. We also found that fibrin can promote the aggregation of Tau in vitro. We hypothesize that fibrin enters the brain parenchyma through the injured blood-brain barrier, and induces the pathological aggregation of tau and the development of stroke cognitive dysfunction. In this study, we will use Tau transgenic mice and Tau knockout mice in combination with molecular biology, cell biology, animal behavior, and histomorphology methods to determine the role of fibrin-induced Tau aggregation in post-stroke cognitive impairment. This study will provide novel targets for the prevention and treatment of post-stroke cognitive impairment.