CDK5-LPL信号通路促进Aβ吞噬及其调控Tau蛋白磷酸化修饰研究

Alzheimer's disease (AD) seriously threatens human's health and the mechanism under its pathogenesis still keeps unclear. Until now, there is no cure or effective treatment drug for AD. Pathological examination revealed the presence of senile plaques consisting of amyloid Aβ, neuritic plaques, and neurofibrillary tangles which is full of Tau proteins in the human brain tissue. In addition, researchers also found lipoprotein, Complement factor in Aβ plaques and activated microglia surrounding Aβ. Microglia plays an important role in the Aβ phagocytosis and clearance. However, it reported less about research on the mechanism under this process. In the previous study, we found that p25 and LPL were increased in the process of Aβ phagocytosis and lead to enhanced CDK5 activity and the phagocytosis ability in microglia for the first time, but the signaling pathway and the mechanism of cross-talk between Aβ phagocytosis and Tau hyper-phosphorylation regulated by CDK5 are kept promising and remain unclear. For Aβ deposition and CDK5 regulatory phosphorylation modification, we intend to use cell line, transgenic animal model, clinical samples, and high-throughput mass spectrometry platform to systematically study the dynamics in the microglia phagocytosis of Aβ, CDK5 function and the signaling network which regulates the phosphorylation modification of Tau protein, then figure out the detailed mechanism and new therapeutic targets, and provide new evidence for AD pathogenesis and therapy.

阿尔茨海默病（AD）严重危害人们的健康，其发病机制尚不清楚并缺乏有效的治疗药物。病理检查发现脑组织中存在由Aβ淀粉样蛋白组成的老年斑、神经炎性斑块和Tau蛋白组成的神经纤维缠结等特征，并在Aβ斑块中发现脂蛋白、补体因子等蛋白以及在Aβ周围活化的小胶质细胞。小胶质细胞在Aβ吞噬和清除过程中起了关键的作用。我们前期研究中首次发现细胞周期依赖激酶CDK5的调节亚基p25和脂蛋白酶LPL在Aβ吞噬过程中上调，导致CDK5活性升高，增强小胶质细胞吞噬Aβ的能力，但CDK5在Aβ吞噬与Tau蛋白过度磷酸化交叉调控作用机制研究未见报道。本课题拟利用细胞、转基因动物模型、临床样本、高通量质谱技术平台，针对Aβ吞噬、CDK5调控的磷酸化修饰，系统研究小胶质细胞在Aβ吞噬过程中蛋白质的动态变化、CDK5功能及其调控Tau蛋白磷酸化修饰的信号网络，发现新的调控靶标和作用机制，为AD发病机制和治疗提供新的依据。

阿尔茨海默病（Alzheimer’s disease, AD）是严重危害人类健康的神经退行性疾病，其最主要的病理特征为老年斑沉积、神经纤维缠结以及神经元的变性死亡。Aβ生成和降解的平衡失调造成的Aβ沉积是AD发病的关键因素。小胶质细胞作为脑中的巨噬细胞能够通过表面膜受体吞噬并降解Aβ，进而减少Aβ沉积，但其分子调控机制并不清楚。本课题利用细胞、转基因动物模型、临床样本、高通量质谱技术平台，针对Aβ吞噬、CDK5调控的磷酸化修饰，系统研究小胶质细胞在Aβ吞噬过程中蛋白质的动态变化、CDK5功能及其调控Tau蛋白磷酸化修饰的信号网络，发现新的调控靶标和作用机制。本项目的成果如下：1）首次揭示激酶CDK5-LPL信号在小胶质细胞吞噬清除淀粉样蛋白Aβ中的功能调控机制；2）首次揭示SIRT1介导的去乙酰化修饰调控溶酶体生成关键转录因子TFEB转录活性，进而增强溶酶体转录活性，进而增强溶酶体生成和功能，并最终促进小胶质细胞降解fAβ的调控机制；3）通过定量磷酸化蛋白质组学手段发现激酶CDK5介导的磷酸化信号调控小胶质细胞的吞噬作用和炎症反应的机制；4）首次发现MAPK信号通路调节因子PEA15调控胶质细胞吞噬Aβ的机制。这些研究成果为进一步深入研究小胶质细胞如何吞噬Aβ，以及小胶质细胞炎症调控在AD发生发展中的功能机制方面提供了重要的实验依据，为揭示AD的发病机理和寻找新的药物靶点提供了重要的科学依据。项目执行期间共在国际学术期刊上发表研究论文8篇（SCI收录，标注基金资助号），获得国家发明专利授权1项，申请国家发明专利2项，培养研究生7名。