基因增强趋化因子 CXCL1 结构域的表达未能预防神经tau 病模型中小鼠的 tau 病理。

Genetically enhancing the expression of chemokine domain of CXCL1 fails to prevent tau pathology in mouse models of tauopathy.

机构信息

Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA.

Kent State University, Kent, OH, 44242, USA.

出版信息

J Neuroinflammation. 2018 Sep 25;15(1):278. doi: 10.1186/s12974-018-1310-6.

DOI:10.1186/s12974-018-1310-6

PMID:30253780

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6154806/

Abstract

BACKGROUND

Fractalkine (CXCL1) and its receptor (CXCR1) play an important role in regulating microglial function. We have previously shown that Cxcr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CXCL1 is essential in regulating neuronal tau pathology.

METHODS

We used transgenic mice lacking endogenous Cxcl1 (Cxcl1) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CXCL1 (referred to as Cxcl1 mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy.

RESULTS

First, increased basal tau levels accompanied microglial activation in Cxcl1 mice compared to control groups. Second, increased CD45 and F4/80 neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cxcl1, and hTau/Cxcl1 mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CXCR1 was reduced in Cxcl1 mice, suggesting enhanced fractalkine receptor internalization (mimicking Cxcr1 deletion), which likely contributes to the elevated tau pathology.

CONCLUSIONS

Collectively, our data suggest that overexpression of only chemokine domain of CXCL1 does not protect against tau pathology.

摘要

背景

趋化因子（CXCL1）及其受体（CXCR1）在调节小胶质细胞功能方面发挥着重要作用。我们之前的研究表明，Cxcr1 缺陷会加剧 tau 病理学并导致认知障碍。然而，配体 CXCL1 的趋化因子结构域是否对调节神经元 tau 病理学至关重要仍不清楚。

方法

我们使用缺乏内源性 Cxcl1（Cxcl1）的转基因小鼠，这些小鼠只表达必需的可溶性形式（只有趋化因子结构域）且缺乏 CXCL1 的粘蛋白茎（称为 Cxcl1 小鼠），以评估 LPS 和 tau 病变的遗传（hTau）小鼠模型中的 tau 病理学和行为功能。

结果

首先，与对照组相比，Cxcl1 小鼠的基础 tau 水平升高，伴有小胶质细胞活化。其次，在 LPS、hTau/Cxcl1 和 hTau/Cxcl1 小鼠 tau 病变模型中，观察到 CD45 和 F4/80 神经炎症和 tau 磷酸化增加，这与空间学习受损有关。最后，Cxcl1 小鼠中 CXCR1 的小胶质细胞表面表达减少，提示 fractalkine 受体内化增强（模拟 Cxcr1 缺失），这可能导致 tau 病理学升高。