TREM2调控小胶质细胞促炎功能参与tau病理的机制研究

Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer’s disease (AD). Emerging clinical evidence suggests that TREM2 is independently associated with tau pathology under AD context, but the underlying mechanisms remain unclear. In our previous studies, we showed for the first time that TREM2 was uniquely expressed by microglia in brain, and might exert a modulatory effect on microglial pro-inflammatory responses. More importantly, we provided the first evidence that knockdown of microglial TREM2 in brain of P301S-tau transgenic mice using a lentiviral-mediated strategy markedly exacerbated neuronal tau pathology. Meanwhile, this exacerbation might be attributed to the hyperactivation of tau kinases. Based on these findings, we hypothesize that TREM2 ameliorates neuronal tau pathology via suppressing the hyperactivation of tau kinases induced by microglial pro-inflammatory responses. In this project, we employ a Transwell microglial-neuronal co-culture system to test this hypothesis. In addition, by using a lentiviral-mediated TREM2 overexpression strategy, we intend to observe the therapeutic effects of TREM2 on tau pathology as well as cognitive deficiency in P301S-tau transgenic mice. The completion of this project will uncover the role of TREM2 in tau pathology during the progression of AD as well as other tauopathies, and will offer novel target for therapies and drug development of these diseases.

TREM2是新发现的AD易感基因。有临床证据表明：其与tau病理独立相关，但机制尚不明确。我们在前期研究中发现：1）TREM2在脑内特异表达于小胶质细胞，并可能对其促炎功能起调控作用；2）在P301S-tau小鼠脑内，沉默小胶质细胞TREM2表达可上调神经元内tau激酶活性，并加剧tau病理严重程度。据此，我们提出“TREM2通过调控小胶质细胞促炎功能，从而下调周边神经元内tau激酶活性，进而延缓tau病理形成”这一假说。在本项目中，我们拟使用Transwell小胶质细胞/神经元共培养系统和基因沉默/过表达技术，对该假说进行验证。在此基础上，我们拟选用P301S-tau小鼠，结合脑内基因转导技术，进一步观察靶向上调TREM2对tau病理及相关认知障碍的治疗作用。本项目的完成能揭示TREM2在tau病理中扮演的角色，还能加深对AD及其他tau蛋白病发病机制的认识，并为它们的治疗提供新的靶点。

TREM2基因是新发现的阿尔茨海默病（Alzheimer' disease, AD）易感基因，有临床证据表明：该基因编码的蛋白与tau病理独立相关，但具体的生物学机制尚不明确。在本项目中，负责人使用Transwell小胶质细胞/神经元非接触共培养系统及AD转基因动物模型，结合慢病毒介导的基因沉默/过表达技术，首次发现TREM2可促使小胶质细胞从“M1型活化态”向“M2型活化态”转化，从而上调小胶质细胞吞噬功能并下调小胶质细胞促炎功能，进而延缓AD病理进程。此外，负责人还发现TREM2的同族蛋白TREM1在脑内亦表达于小胶质细胞，其可通过增强小胶质细胞对Aβ的吞噬从而阻止淀粉样斑块在脑内沉积。上述研究成果不仅加深了对AD发病机制的认识，还为该病的治疗提供了全新的靶点和相关理论依据。