CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling

Meng, Fanyong; Guo, Zhige; Hu, Yaling; Mai, Weihao; Zhang, Zhenjie; Zhang, Bin; Ge, Qianqian; Lou, Huifang; Guo, Fang; Chen, Jiang‐Fan; Duan, Shumin; Gao, Zhihua

doi:10.1093/brain/awy351

Cited by 77 publications

(71 citation statements)

References 97 publications

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“…A recent study indicated that the extracellular CD73‐mediated formation of adenosine provides an important source for the activation of A2AR, as demonstrated by the coordinated overexpression of CD73 and A2AR in Parkinson's disease models . In the present study, we observed overexpression of CD73 in the specimens of RE, implicating that increased CD73‐mediated adenosine formation might contribute to the activation of A2ARs in RE.…”

Section: Increased Immunoreactivity Of A2ars In Resupporting

confidence: 76%

Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis

Chen

Zhang

et al. 2019

Brain Pathology

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Rasmussen encephalitis (RE) is a severe pediatric inflammatory brain disease characterized by unilateral inflammation and atrophy of the cerebral cortex, drug‐resistant focal epilepsy and progressive neurological and cognitive deterioration. The etiology and pathogenesis of RE remain unclear. Our previous results demonstrated that the adenosine A1 receptor (A1R) and the major adenosine‐removing enzyme adenosine kinase play an important role in the etiology of RE. Because the downstream pathways of inhibitory A1R signaling are modulated by stimulatory A2AR signaling, which by itself controls neuro‐inflammation, glial activation and glial glutamate homeostasis through interaction with glutamate transporter GLT‐1, we hypothesized that maladaptive changes in adenosine A2A receptor (A2AR) expression are associated with RE. We used immunohistochemistry and Western blot analysis to examine the expression of A2ARs, glutamate transporter‐I (GLT‐1) and the apoptotic marker Bcl‐2 in surgically resected cortical specimens from RE patients (n = 18) in comparison with control cortical tissue. In lesions of the RE specimen we found upregulation of A2ARs, downregulation of GLT‐1 and increased apoptosis of both neurons and astroglia. Double staining revealed colocalization of A2ARs and Bcl‐2 in RE lesions. These results suggest that maladaptive changes in A2AR expression are associated with a decrease in GLT‐I expression as a possible precipitator for apoptotic cell loss in RE. Because A2AR antagonists are already under clinical evaluation for Parkinson's disease, the A2AR might likewise be a tractable target for the treatment of RE.

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Section: Increased Immunoreactivity Of A2ars In Resupporting

confidence: 76%

Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis

Chen

Zhang

et al. 2019

Brain Pathology

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“…Although the source of the adenosine responsible for the over-activation of A 2A receptors has not been determined, the recently described tight physical and functional coupling between A 2A receptors and CD73 or ecto-5′-nucleotidase (the enzyme forming adenosine from extracellular adenine nucleotides) in the striatum (Augusto et al, 2013;Ena, De Backer, Schiffmann, & de Kerchove d'Exaerde, 2013) prompts the hypothesis that the release of ATP as a stress signal might be the source of the adenosine responsible for the over-activation of A 2A receptors contributing to the development of PD. Furthermore, there is previous evidence to suggest that extracellular ATP increases neurodegeneration (see Rodrigues et al, 2015) and that the activity of CD73 can affect neurodegeneration (Boeck, Kroth, Bronzatto, & Vendite, 2007;Meng et al, 2019) both directly through the control of neuronal survival (Heilbronn, Maienschein, Carstensen, Gann, & Zimmermann, 1995) and indirectly through its ability to control inflammatory responses (see Antonioli, Pacher, Vizi, & Haskó, 2013).…”

Section: Introductionmentioning

confidence: 99%

Enhanced ATP release and CD73‐mediated adenosine formation sustain adenosine A_2A receptor over‐activation in a rat model of Parkinson's disease

Carmo

Gonçalves

Canas

et al. 2019

British J Pharmacology

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Background and Purpose Parkinson's disease (PD) involves an initial loss of striatal dopamine terminals evolving into degeneration of dopamine neurons in substantia nigra (SN), which can be modelled by 6‐hydroxydopamine (6‐OHDA) administration. Adenosine A2A receptor blockade attenuates PD features in animal models, but the source of the adenosine causing A2A receptor over‐activation is unknown. As ATP is a stress signal, we have tested if extracellular catabolism of adenine nucleotides into adenosine (through ecto‐5′‐nucleotidase or CD73) leads to A2A receptor over‐activation in PD. Experimental Approach Effects of blocking CD73 with α,β‐methylene ADP (AOPCP) were assayed in 6‐OHDA‐treated rats and dopamine‐differentiated neuroblastoma SH‐SY5Y cells. Key Results 6‐OHDA increased ATP release and extracellular conversion into adenosine through CD73 up‐regulation in SH‐SY5Y cells. Removing extracellular adenosine with adenosine deaminase, blocking CD73 with AOPCP, or blocking A2A receptors with SCH58261 were equi‐effective in preventing 6‐OHDA‐induced damage in SH‐SY5Y cells. In vivo striatal exposure to 6‐OHDA increased ATP release and extracellular formation of adenosine from adenosine nucleotides and up‐regulated CD73 and A2A receptors in striatal synaptosomes. Intracerebroventricular administration of AOPCP phenocopied effects of SCH58261, attenuating 6‐OHDA‐induced (a) increase of contralateral rotations after apomorphine, (b) reduction of dopamine content in striatum and SN, (c) loss of TH staining in striatum and SN, (d) motor dysfunction in the cylinder test, and (e) short‐term memory impairment in the object recognition test. Conclusion and Implications Our data indicate that increased ATP‐derived adenosine formation is responsible for A2A receptor over‐activation in PD, suggesting CD73 as a new target to manage PD.

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“…CD73 is a glycoprotein that functions as exogeneous-5'-nucleotidase and participates in signal transduction. CD73 hydrolyzes 5'-adenosine monophosphate (AMP) into adenosine and phosphoric acid and then interacts with adenosine receptors on the cell surface to regulate many biological effects [26]. CD73 also has non-hydrolase function, which is also a signal and adhesion molecule that regulate cell-extracellular matrix interaction [27].…”

Section: Discussionmentioning

confidence: 99%

CD73 positive adipose derived mesenchymal stem cells enhance cardiac repair with experimental myocardial infarction by promoting angiogenesis

Li¹,

Hou

et al. 2020

Preprint

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Background: Cardiovascular disease is the leading cause of death in developed and developing countries. The lack of effective regenerative therapies in the treatment of ischemia‐related diseases requires new therapies to improve clinical outcomes. Thus, MSCs have become a focus in stem cell treatment of myocardial injury. At present, most studies use mixed MSCs in vivo and in vitro. A promising therapeutic strategy for myocardial injury should be using the dominant subgroup with essential biological characteristics. The aim of this study was to utilize the dominant CD73 + subgroup of adipose derived mesenchymal stem cells (ADMSCs) for the therapy of myocardial infarction (MI). Methods: Adult mix gender SD rats, with a body weight of 230±18g, were randomly divided into sham operation group (SHAM), MI group (MI), mixed ADMSCs transplantation group (MI+ADMSCs), CD73 + ADMSCs transplantation group (MI+CD73 + ADMSCs) and CD73 - ADMSCs transplantation group (MI+CD73 - ADMSCs). CD73 + ADMSCs were isolated using flow cytometry and then cultured. Overexpression and inhibition of CD73 gene of ADMSCs using lentiviral vectors. Differential genes analysis of CD73 + ADMSCs vs. CD73 - ADMSCs were based on GO analysis. The effect of CD73 on the secretion of cytokines was measured by ELISA. Myocardial infarction model and cell transplantation model were replicated. Detection of cardiac function of rats by color doppler ultrasound after operation. The expression of VEGF and factor VIII and neovascularization were detected by immunohistochemistry and Western Blotting. Results: We demonstrated that, compared to mixed ADMSCs and CD73 - ADMSCs, CD73 + ADMSCs were more effective in the promotion function of cardiac recovery in a rat model of MI. CD73 + subset promoted vascular regeneration in myocardial injured regions. We also showed that expression of CD73 promoted secretion of VEGF, HIF-1α and HGF factors in ADMSCs. CD73 + ADMSCs displayed significantly different transcription profile compared to CD73 - ADMSCs, in particular, concerning VEGF pathways. Conclusions: Overall, CD73 + ADMSCs were the dominant subgroup and the presence of the surface marker CD73 can be used as a MSCs cell quality control for treatment of myocardial injury by angiogenesis.

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CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling

Cited by 77 publications

References 97 publications

Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis

Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis

Enhanced ATP release and CD73‐mediated adenosine formation sustain adenosine A_2A receptor over‐activation in a rat model of Parkinson's disease

CD73 positive adipose derived mesenchymal stem cells enhance cardiac repair with experimental myocardial infarction by promoting angiogenesis

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CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling

Cited by 77 publications

References 97 publications

Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis

Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis

Enhanced ATP release and CD73‐mediated adenosine formation sustain adenosine A2A receptor over‐activation in a rat model of Parkinson's disease

CD73 positive adipose derived mesenchymal stem cells enhance cardiac repair with experimental myocardial infarction by promoting angiogenesis

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Enhanced ATP release and CD73‐mediated adenosine formation sustain adenosine A_2A receptor over‐activation in a rat model of Parkinson's disease