2. Academic Validation
  3. Inhibition of ADORA3 promotes microglial phagocytosis and alleviates chronic ischemic white matter injury

Inhibition of ADORA3 promotes microglial phagocytosis and alleviates chronic ischemic white matter injury

  • CNS Neurosci Ther. 2024 May;30(5):e14742. doi: 10.1111/cns.14742.
Yuhao Xu 1 2 3 4,  Limoran Tang 1 2 3 4,  Chao Zhou 1 2 3 4,  Liang Sun 1 2 3 4,  Yujie Hu 1 2 3 4,  Zhi Zhang 1 2 3 4,  Shengnan Xia 1 2 3 4,  Xinyu Bao 1 2 3 4,  Haiyan Yang 1 2 3 4,  Yun Xu 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China.
  • 3 Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
  • 4 Nanjing Neurology Clinical Medical Center, Nanjing, China.
PMID: 38715283 DOI: 10.1111/cns.14742
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: ADORA3 antagonist alleviates chronic ischemic WMI by modulating myelin clearance of microglia, which may be a potential therapeutic target for the treatment of VaD.

Keywords

Mertk; adenosine A3 receptor; microglia; phagocytosis; vascular dementia; white matter injury.

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