LRRK2调节阿尔茨海默病小胶质细胞异常免疫调控Tau病理发生的机制

近年以纠正小胶质细胞免疫异常为靶标的策略成为阿尔茨海默病(AD)防治的重要方向。LRRK2高表达于海马和纹状体等关键脑区,参与免疫调控,但其如何通过调节免疫系统影响AD-Tau病理的机制不清。我们前期分子筛选发现LRRK2-G2019S突变鼠小胶质细胞AD易感免疫基因ABCA7/CD33等mRNA明显高表达,AD:G2019S杂交鼠海马Tau磷酸化增强伴认知运动异常加剧,但机制不清。我们推测“LRRK2通过调节AD小胶质细胞免疫信号影响Tau病理进程”是AD免疫致病新机制。本研究构建AD鼠LRRK2-G2019S突变模型(5xFAD;G2019S)、小胶质细胞LRRK2条件敲除小鼠的人AD脑脊液病理Tau注射模型,应用分子生物/免疫病理等技术,从整体-细胞-分子水平验证上述假说,揭示LRRK2调节小胶质细胞免疫异常促发Tau病理的分子机制,为LRRK2为靶点防治AD脑免疫紊乱提供新思路。

More recently, microglia play specific roles in determining progression and outcomes of many neurodegenerative diseases and has now taken center stage as a therapeutic target. The strategy to correct abnormalities of microglial immune has become an important direction of Alzheimer's disease (AD). LRRK2 is highly expressed in key brain regions such as the hippocampus and striatum, which is involved in regulation of cognition and motor function. LRRK2 is also involved in immune pathogenesis and Tau pathology, but it remain unknown that how LRRK2 impacts Alzheimer's disease (AD), especially modulation of LRRK2 on the immune system mediated Tau pathogenesis in AD. Of note, using q-PCR screen, our preliminary study confirmed that LRRK2-G2019S mutantion significantly elevated the mRNAs levels of AD-microglial susceptible immunogenes e.g. ABCA7, CD33 and so on, in hippocampus of mice. Meanwhile, AD: LRRK2-G2019S hybrid transgenic mice had enhanced Tau phosphorylation in hippocampus, which accompanied with abnormally deteriorated motor and cognitive behaviors, however, of which the mechanism is unclear. These findings prompt us to explore the molecular mechanism by which LRRK2 regulates AD-related microglial immunoreceptors and their signaling pathways in triggering the Tau pathogenesis of AD. We sepeculate that "LRRK2 impacts the Tau pathological progression by regulating AD-microglial immune receptors function and signaling pathaway" is a novel mechanism for the immunopathogenesis for AD. In this study, to address this issue, we setup a hybrid mouse model that LRRK2-G2019S mutation crossed with a 5xFAD dementia transgenic mouse (5xFAD;G2019S), using a LRRK2 targeted pharmacological inhibition model, and injection of human CSF pathologic Tau-derived from AD patients (AD-Tau) in the microglial LRRK2 conditioned knockout mice model, to verify our hypothesis. We will perform the experiments from the level of animal, cells and molecules using the molecular immunopathology, biotechnology, bioinformatics and confocal microscope analysis, etc. The present study will support the hypothesis that LRRK2-mediated AD-microglial immune function and signaling in regulating Tau pathogenesis, which may play a crucial role in activated microglia-induced Tau pathology of AD. The research will provide new ideas for LRRK2 as a target for preventing and treating AD-related immune disorders.