Perivascular AQP4 dysregulation in the hippocampal CA1 area after traumatic brain injury is alleviated by adenosine A(2A) receptor inactivation.
Perivascular AQP4 dysregulation in the hippocampal CA1 area after traumatic brain injury is alleviated by adenosine A(2A) receptor inactivation.
复制标题
腺苷 A(2A) 受体失活可缓解创伤性脑损伤后海马 CA1 区血管周围 AQP4 失调
DOI：
10.1038/s41598-017-02505-6
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发表时间：
2017-05-22
影响因子：
4.6
通讯作者：
Zhou YG
中科院分区：
文献类型：
--
作者：
Zhao ZA;Li P;Ye SY;Ning YL;Wang H;Peng Y;Yang N;Zhao Y;Zhang ZH;Chen JF;Zhou YG
创伤性脑损伤（TBI）可由于过度磷酸化的tau蛋白（p-tau）的区域积累而引起认知功能障碍。然而，导致p-tau集中在特定大脑区域的因素仍不清楚。在这里，我们表明，AQP 4极化血管周围的星形胶质细胞端脚受损后，TBI，这是最突出的同侧脑组织周围的直接影响的地区和对侧海马CA 1区，并伴随着增加本地p-tau，树突棘密度和形态的变化，和上调的腺苷A2 A受体（A2 AR）。A2 AR信号转导在这些病理变化中的关键作用通过A2 AR敲除小鼠中AQP 4极性的损伤和对侧CA 1区中p-tau的积累的减轻而被证实。考虑到p-tau蛋白可以释放到细胞外空间，并且星形胶质细胞通过AQP 4的水转运参与了tau蛋白从脑皮质的清除，我们的研究结果表明，TBI后AQP 4极性的区域破坏可能会减少毒性间质溶质如p-tau蛋白的清除，并导致树突棘密度和形态的变化。这可以解释为什么TBI患者更容易出现认知功能障碍。
Traumatic brain injury (TBI) can induce cognitive dysfunction due to the regional accumulation of hyperphosphorylated tau protein (p-tau). However, the factors that cause p-tau to concentrate in specific brain regions remain unclear. Here, we show that AQP4 polarization in the perivascular astrocytic end feet was impaired after TBI, which was most prominent in the ipsilateral brain tissue surrounding the directly impacted region and the contralateral hippocampal CA1 area and was accompanied by increased local p-tau, changes in dendritic spine density and morphology, and upregulation of the adenosine A2A receptor (A2AR). The critical role of the A2AR signaling in these pathological changes was confirmed by alleviation of the impairment of AQP4 polarity and accumulation of p-tau in the contralateral CA1 area in A2AR knockout mice. Given that p-tau can be released to the extracellular space and that the astroglial water transport via AQP4 is involved in tau clearance from the brain interstitium, our results suggest that regional disruption of AQP4 polarity following TBI may reduce the clearance of the toxic interstitial solutes such as p-tau and lead to changes in dendritic spine density and morphology. This may explain why TBI patients are more vulnerable to cognitive dysfunction.