PDF(Pubmed)
Abstract：
Adenosine A3 receptor (ADORA3) belongs to the adenosine receptor families and the role of ADORA3 in vascular dementia (VaD) is largely unexplored. The present study sought to determine the therapeutic role of ADORA3 antagonist in a mouse model of VaD.
The GSE122063 dataset was selected to screen the differential expression genes and pathways between VaD patients and controls. A mouse model of bilateral carotid artery stenosis (BCAS) was established. The cognitive functions were examined by the novel object recognition test, Y maze test, and fear of conditioning test. The white matter injury (WMI) was examined by 9.4 T MRI, western blot, and immunofluorescence staining. The mechanisms of ADORA3-regulated phagocytosis by microglia were examined using qPCR, western blot, dual immunofluorescence staining, and flow cytometry.
The expression of ADORA3 was elevated in brain tissues of VaD patients and ADORA3 was indicated as a key gene for VaD in the GSE122063. In BCAS mice, the expression of ADORA3 was predominantly elevated in microglia in the corpus callosum. ADORA3 antagonist promotes microglial phagocytosis to myelin debris by facilitating cAMP/PKA/p-CREB pathway and thereby ameliorates WMI and cognitive impairment in BCAS mice. The therapeutic effect of ADORA3 antagonist was partially reversed by the inhibition of the cAMP/PKA pathway.
ADORA3 antagonist alleviates chronic ischemic WMI by modulating myelin clearance of microglia, which may be a potential therapeutic target for the treatment of VaD.
The GSE122063 dataset was selected to screen the differential expression genes and pathways between VaD patients and controls. A mouse model of bilateral carotid artery stenosis (BCAS) was established. The cognitive functions were examined by the novel object recognition test, Y maze test, and fear of conditioning test. The white matter injury (WMI) was examined by 9.4 T MRI, western blot, and immunofluorescence staining. The mechanisms of ADORA3-regulated phagocytosis by microglia were examined using qPCR, western blot, dual immunofluorescence staining, and flow cytometry.
The expression of ADORA3 was elevated in brain tissues of VaD patients and ADORA3 was indicated as a key gene for VaD in the GSE122063. In BCAS mice, the expression of ADORA3 was predominantly elevated in microglia in the corpus callosum. ADORA3 antagonist promotes microglial phagocytosis to myelin debris by facilitating cAMP/PKA/p-CREB pathway and thereby ameliorates WMI and cognitive impairment in BCAS mice. The therapeutic effect of ADORA3 antagonist was partially reversed by the inhibition of the cAMP/PKA pathway.
ADORA3 antagonist alleviates chronic ischemic WMI by modulating myelin clearance of microglia, which may be a potential therapeutic target for the treatment of VaD.
摘要：
背景：腺苷A3受体（ADORA3）属于腺苷受体家族，ADORA3在血管性痴呆（VaD）中的作用尚未被研究。本研究试图确定ADORA3拮抗剂在VaD小鼠模型中的治疗作用。
方法：选择GSE122063数据集来筛选VaD患者和对照组之间的差异表达基因和通路。建立双侧颈动脉狭窄(BCAS)小鼠模型。通过新颖的物体识别测试检查了认知功能，Y迷宫测试,和对条件测试的恐惧。通过9.4TMRI检查白质损伤（WMI），westernblot,和免疫荧光染色。使用qPCR检查了小胶质细胞ADORA3调节吞噬作用的机制，westernblot,双重免疫荧光染色，和流式细胞术。
结果：VaD患者脑组织中ADORA3的表达升高，在GSE122063中，ADORA3是VaD的关键基因。在BCAS小鼠中,ADORA3的表达主要在call体的小胶质细胞中升高。ADORA3拮抗剂通过促进cAMP/PKA/p-CREB途径促进小胶质细胞吞噬髓鞘碎片，从而改善BCAS小鼠的WMI和认知障碍。ADORA3拮抗剂的治疗作用被cAMP/PKA途径的抑制部分逆转。
结论：ADORA3拮抗剂通过调节小胶质细胞的髓鞘清除减轻慢性缺血性WMI，这可能是治疗VaD的潜在治疗靶点。
方法：选择GSE122063数据集来筛选VaD患者和对照组之间的差异表达基因和通路。建立双侧颈动脉狭窄(BCAS)小鼠模型。通过新颖的物体识别测试检查了认知功能，Y迷宫测试,和对条件测试的恐惧。通过9.4TMRI检查白质损伤（WMI），westernblot,和免疫荧光染色。使用qPCR检查了小胶质细胞ADORA3调节吞噬作用的机制，westernblot,双重免疫荧光染色，和流式细胞术。
结果：VaD患者脑组织中ADORA3的表达升高，在GSE122063中，ADORA3是VaD的关键基因。在BCAS小鼠中,ADORA3的表达主要在call体的小胶质细胞中升高。ADORA3拮抗剂通过促进cAMP/PKA/p-CREB途径促进小胶质细胞吞噬髓鞘碎片，从而改善BCAS小鼠的WMI和认知障碍。ADORA3拮抗剂的治疗作用被cAMP/PKA途径的抑制部分逆转。
结论：ADORA3拮抗剂通过调节小胶质细胞的髓鞘清除减轻慢性缺血性WMI，这可能是治疗VaD的潜在治疗靶点。
