Adenosine A(2A) Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury.
Adenosine A(2A) Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury.
复制标题
骨髓来源细胞中的腺苷 A(2A) 受体可减轻慢性低灌注白质损伤后小鼠的认知障碍。
DOI：
10.1007/s12975-019-00778-9
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发表时间：
2020
影响因子：
6.9
通讯作者：
Zhou Zhenhua
中科院分区：
文献类型：
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作者：
Ran Hong;Yuan Jichao;Huang Jialu;Wang Jie;Chen Kangning;Zhou Zhenhua
缺血性脑白质损伤引起认知功能障碍的机制尚不清楚。为了探讨不同细胞源性腺苷a2a受体（A2AR）在慢性低灌注白质病变（CHWMLs）所致认知功能障碍中的作用和机制，我们采用辐射照射破坏受体小鼠骨髓造血能力，然后将A2AR基因敲除或野生型小鼠的骨髓分别移植到野生型或基因敲除小鼠中，建立选择性灭活或重组A2AR模型。采用Morris水迷宫法（MWM）、ELISA法、免疫组织化学法、Bielschowsky银染色法观察慢性脑血流灌注不足（CCH）模型大鼠认知功能的影响及机制。选择性重建骨髓源性细胞（bmdc） A2AR （WT→KO组）和用CGS21680激活总腺苷A2AR （CCH + CGS组）可改善认知相关指标。激活BMDC A2AR可抑制外周血炎症因子的表达，减少脑局部与胱抑素F共定位的活化小胶质细胞的数量，从而抑制白质病变。相反，腺苷A2AR选择性失活（KO→WT组）和CGS21680激活非bmdc A2AR （KO→WT + CGS组）具有相反的效果。上述结果表明，BMDC - A2AR可抑制脑白质病变，减轻脑脑损伤后的认知功能障碍，而非BMDC - A2AR可加重脑脑损伤后的认知功能障碍。全身炎症反应和高表达胱抑素F的局部激活小胶质细胞参与了BMDC A2AR治疗认知功能恢复的过程。总体趋势是BMDC a2ar发挥主导作用。
The mechanism of cognitive dysfunction caused by ischemic white matter lesions is unclear. To explore the effect and mechanism of different cell-derived adenosine A2Areceptor (A2AR) in cognitive impairment caused by chronic hypoperfusion white matter lesions (CHWMLs), we destroyed the bone marrow hematopoietic capacity of the recipient mice using radiation irradiation followed by establishing the selectively inactivated or reconstituted A2AR models with the transplanting bone marrow from global A2AR gene knockout or wild-type mice into wild-type or gene knockout mice, respectively. Then Morris Water Maze (MWM), ELISA, immunohistochemistry, and Bielschowsky silver staining were used to assess the effect and mechanism of the cognitive function in chronic cerebral blood flow hypoperfusion (CCH) model. Selectively reconstructing bone marrow-derived cells (BMDCs) A2AR (WT → KO group) and activated total adenosine A2AR with CGS21680 (CCH + CGS group) improved the cognitive related index. Activation of BMDC A2AR suppressed expression of inflammatory cytokines in peripheral blood and reduced the number of activated microglia cells co-localized with cystatin F in local brain, consequently inhibited white matter lesions. On the contrary, selective inactivation of adenosine A2AR (KO → WT group) and activation of non-BMDC A2AR with CGS21680 (KO → WT + CGS group) served the opposite effects. These results suggested that BMDC A2AR could inhibit white matter lesions and attenuate cognitive impairment after CHWMLs, whereas non-BMDC A2ARs aggravate cognitive impairment. The systemic inflammatory response and local activated microglia with cystatin F high expression were involved in the process of cognitive function recovery with BMDC A2AR. The overall trend is that BMDC A2ARs play a leading role.