LPA-legumain通路介导血管性痴呆发病机制的研究

The prevalence of cognitive dysfunction is very high in ischemic stroke survivors. It substantially affects the quality of life in those patients. However, the pathogenesis of cognitive dysfunction after ischemic stroke remains elusive. In our previous experiments we found that legumain cleaves amyloid precursor protein (APP) and tau, promoting Aβ deposition, tau phosphorylation, and cognitive impairments. Furthermore, the concentration of lysophosphatidic acid (LPA) increases after ischemic stroke, which activates the enzymatic activity of legumain. We hypothesize that ischemic brain injury promote LPA production, which binds and activates legumain, leading to the cleavage of APP and tau, and finally cause cognitive dysfunction. In the present project, we will make the in vitro and in vivo models of ischemic stroke, and investigate the role LPA-legumain pathway in cognitive dysfunction using biochemical, molecular biology, animal ethology and electrophysiology methods. The results of the current project will help us to understand the major pathological pathway of cognitive impairments and dementia after stroke, and provide novel target for the diagnosis and treatment for this devastating disease.

缺血性脑血管病导致的认知功能障碍发病率高，严重影响患者的生存质量，但其发病机制未明。申请人前期研究发现legumain能够剪切淀粉样前体蛋白（APP）和tau蛋白，促进Aβ沉积和tau蛋白磷酸化，参与认知功能障碍的发病，而且缺血性脑血管病发生后溶血磷脂酸（LPA）水平增高，LPA能够增强legumain活性。据此我们提出假说：缺血性脑血管病发生后局部增高的LPA结合并激活legumain，legumain剪切APP和tau蛋白，导致Aβ沉积和tau蛋白磷酸化，导致认知功能障碍的发生。本课题中，我们将制作在体和离体脑缺血模型，采用一系列生物化学、分子生物学、动物行为学和电生理学等研究方法，探索LPA-legumain这一通路在缺血性脑血管病后认知功能障碍和痴呆发生中的作用，阐明脑缺血后认知功能障碍的主要发病机制，为深入研究血管性痴呆的发生提供新的分子靶标。

缺血性脑血管病导致的认知功能障碍发病率高，严重影响患者的生存质量，但其发病机制未明。我们在本研究中发现缺血缺氧状态下神经系统内溶血磷脂酸（LPA）增高，通过其受体激活蛋白酶legumain，legumain剪切tau蛋白，促进tau蛋白的磷酸化和聚集，导致认知功能障碍的发生，阻断LPA/legumain通路能够减轻缺血性脑血管病导致的神经损伤。本研究发现LPA/legumain通路可能是卒中后认知功能障碍的重要发病机制和治疗靶点。