小胶质细胞介导的天然免疫在脑衰老和神经退行性变中的作用

"Microgliopathy", the dysfunction of microglia, is a newly proposed pathologically characteristic of aging and the neurodegenerative diseases such as Alzheimer’s disease (AD). The molecules associated with "microgliopathy" are the myeloid cell-triggered receptor-2 (TREM2) and the colony-stimulating factor-1 receptor (CSF1R), both of which are specifically expressed on microglia and are significantly elevated in neuronal aging and AD patient brain. Both TREM2 and CSF1R mutants cause neurodegenerative disorders characterized by adult-onset dementia. Studies have shown that CSF1R is also necessary for the development, survival and homeostasis of microglia. Our latest published studies have demonstrated that TREM2 plays critical roles in regulating the survival and function of microglia. Our recent preliminary studies have shown that TREM2 interacts with CSF1R using immunoprecipitation assay, and TREM2 is necessary for CSF1R-mediated microglia survival. Furthermore, we found that there were complementary effects on the function of these two receptors in microglia. However, how TREM2 and CSF1R support the function of microglia in protecting against AD and the specific mechanism and role of these two receptors interaction in AD pathogenesis remain largely unknown. Thus, in the current proposal, we plan to dissect how TREM2 interacts with CSF1R in HEK293T cells and the molecular mechanisms underlying the interaction in microglial function using microglia derived from in our novel Csf1r or Trem2 deficient mouse models. Moreover, we plan to explore the significance of the interaction in microglial function in Csf1r or Trem2 deficient 5 × FAD mouse models. We aim to reveal whether the interaction protect against cognitive decline, synaptic dysfunctions and amyloid pathology in AD pathogenesis. Together, our proposed studies will uncover molecular and cellular mechanisms associated with TREM2/CSF1R mediated protection against brain aging and neurodegeneration, thereby nominating new strategies for the therapy.

最新提出“小胶质病理”是多种脑衰老相关神经退行性疾病的共同病理特征，其致病分子主要为脑中小胶质细胞上特异性表达的髓细胞触发受体-2（TREM2）和集落刺激因子1受体（CSF1R），携带TREM2或CSF1R突变体的患者均表现为成年起病的痴呆。我们已发表的研究表明TREM2在小胶质细胞存活和功能调控中起关键作用。最近又发现TREM2和CSF1R在衰老和神经退行性变模型鼠脑中均表达异常，且通过免疫共沉淀发现两者之间存在相互作用。但两者间如何相互作用，其功能异常如何参与脑衰老和神经退行性变中“小胶质病理”进程尚不明确。本项目拟利用Csf1r-/-小鼠和Trem2-/-小鼠及5×FAD转基因小鼠等深入剖析TREM2与CSF1R相互作用的分子机制，阐明两者如何共同调控小胶质细胞天然免疫功能效应，揭示其功能异常在衰老和神经退行性变“小胶质病理”进程中的意义，为延缓脑衰老和神经退行性变提示新的分子靶点。

最新提出“小胶质病理”是多种脑衰老相关神经退行性疾病的共同病理特征，其致病分子主要为脑中小胶质细胞上特异性表达的髓细胞触发受体-2（TREM2）和集落刺激因子1受体（CSF1R），携带TREM2或CSF1R突变体的患者均表现为成年起病的痴呆。我们已发表的研究表明TREM2在小胶质细胞存活和功能调控中起关键作用，且TREM2与CSF1R之间可能存在相互作用。但是，TREM2与CSF1R是否存在相互作用以及这种相互作用如何介导小胶质细胞的存活和功能状态，其功能异常如何参与衰老和神经退行性变过程中“小胶质病理”的形成尚不明确，我们以原代培养小胶质细胞、5×FAD转基因小鼠、Trem2-/-小鼠和Csf1r-/-小鼠等生物学模型为研究对象，深入剖析衰老相关基因TREM2与CSF1R之间确实存在相互作用，并证实了CSF1R和TREM2相互作用于细胞表面及跨膜结构域。我们进而用CSF1R的配体CSF1处理Trem2敲除的小胶质细胞，观察其下游信号通路激活情况，发现在小胶质细胞中β-catenin的稳定性依赖于TREM2的表达，但是，TREM2的缺失并不会影响CSF1激活小胶质细胞中CSF1R磷酸化和及其下游Akt磷酸化。鉴于CSF1R和Akt是调控细胞存活的重要分子，于是我们进一步通过体内和体外实验证实了CSF1可以改善Trem2敲除小鼠中小胶质细胞的存活以及Trem2-/-; 5XFAD小鼠脑中Aβ淀粉样斑的沉积。本研究揭示了CSF1R和TREM2二者共同调控的小胶质细胞参与中枢衰老和神经退行性变病理进程的分子机制，阐明了小胶质细胞功能异常参与衰老和神经退行性变过程的临床意义，为中枢衰老和神经退行性变相关疾病的治疗提示新的分子靶点。