Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

Hu, Qidi; Ren, Xiaojun; Liu, Ya; Li, Zhihui; Zhang, Liping; Chen, Xingjun; He, Chaoxiang; Chen, Jiang‐Fan

doi:10.1016/j.expneurol.2016.05.040

Cited by 50 publications

(56 citation statements)

References 102 publications

(159 reference statements)

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“…Notably, we found a major ectopic expression of the A2AR in the cytoplasm of neurons and astrocytes. These unexpected findings are in line with the literature describing ectopic overexpression of A2ARs in the cytoplasm of neurons and astrocytes in pathological situations such as models for Alzheimer's and Parkinson's disease . The role and pathological implications of cytoplasmic A2AR expression are currently unknown.…”

Section: Increased Immunoreactivity Of A2ars In Resupporting

confidence: 88%

“…In line with those findings, the increased expression of astroglial A2ARs in RE might additionally affect cognitive function through a novel mechanism involving astrocyte-driven neuronal adaptation processes (28). The effects of A2ARs on memory are based on the ability of A2ARs to affect working memory and especially reference memory performance (23). Overexpression of A2ARs and the pharmacological activation of A2ARs are sufficient to trigger memory impairment (13).…”

Section: Increased Immunoreactivity Of A2ars In Rementioning

confidence: 69%

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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: 88%

Section: Increased Immunoreactivity Of A2ars In Rementioning

confidence: 69%

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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“…In contrast, neurodegenerative conditions are known to increase activation of NMDA receptors and calcium‐permeable AMPA receptors, leading to hippocampal synaptic plasticity impairment (Diógenes et al ., ; Ferreira et al, ; Tanqueiro et al ., ). There is plenty of evidence that under pathological conditions, A 2A receptor signalling is exacerbated, which contributes to pathogenesis and leads to early cognitive and synaptic dysfunction as well as neurodegeneration (Canas et al ., ; Cognato et al, ; Batalha et al, ; Kadowaki‐Horita et al, ; Kaster et al, ; Li et al, ,b; Hu et al, ; Laurent et al, ; Viana da Silva et al, ). Under such pathological conditions, A 2A receptor blockade restores learning and/or memory (Canas et al, ; Cognato et al, ; Batalha et al, ; Kadowaki‐Horita et al, ; Kaster et al, ; Li et al, ; Viana da Silva et al, ).…”

Section: Discussionmentioning

confidence: 99%

Adenosine A_2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons

Mouro

Rombo

Dias

et al. 2018

British J Pharmacology

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Background and PurposeNMDA receptors play a key role in both synaptic plasticity and neurodegeneration. Adenosine is an endogenous neuromodulator and through membrane receptors of the A2A subtype can influence both synaptic plasticity and neuronal death. The present work was designed to evaluate the influence of adenosine A2A receptors upon NMDA receptor activity in CA1 hippocampal neurons. We discriminated between modulation of synaptic versus extrasynaptic receptors, since extrasynaptic NMDA receptors are mostly associated with neurodegeneration while synaptic NMDA receptors are linked to plasticity phenomena.Experimental ApproachWhole‐cell patch‐clamp recordings were obtained to evaluate NMDA receptor actions on CA1 pyramidal neurons of young adult (5–10 weeks) male Wistar rat hippocampus.Key ResultsActivation of A2A receptors with CGS 21680 (30 nM) consistently facilitated chemically‐evoked NMDA receptor‐currents (NMDA‐PSCs) and afferent‐evoked NMDA‐currents (NMDA‐EPSCs), an action prevented by an A2A receptor antagonist (SCH58261, 100 nM) and a PKA inhibitor, H‐89 (1 μM). These actions did not reflect facilitation in glutamate release since there was no change in NMDA‐EPSCs paired pulse ratio. A2A receptor actions were lost in the presence of an open‐channel NMDA receptor blocker, MK‐801 (10 μM), but persisted in the presence of memantine, at a concentration (10 μM) known to preferentially block extrasynaptic NMDA receptors.Conclusion and ImplicationsThese results show that A2A receptors exert a positive postsynaptic modulatory effect over synaptic, but not extrasynaptic, NMDA receptors in CA1 neurons and, therefore, under non‐pathological conditions may contribute to shift the dual role of NMDA receptors towards enhancement of synaptic plasticity.

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“…In physiological conditions, A 2A Rs play an important role in fine synaptic tuning (Cunha, 2016): neuronal A 2A Rs regulated NMDA receptors to control synaptic plasticity processes (Rebola et al, 2008;Temido-Ferreira et al, 2018) while astrocytic A 2A Rs control glutamate and GABA uptakes (Lopes et al, 2002;Matos et al, 2012Matos et al, , 2013Cristovao-Ferreira et al, 2013), regulating the excitatory/inhibitory balance. Interestingly, reactive astrocytes have been shown to exhibit adenosine A 2A R upregulation in different neuropathological conditions such as AD, epilepsy, Sandhoff disease, and also in animal models of AD and PD (Orr et al, 2015(Orr et al, , 2018Barros-Barbosa et al, 2016;Zhao et al, 2017;Faivre et al, 2018;Lee et al, 2018;Yu et al, 2008;Hu et al, 2016;Ogawa et al, 2018). However, the pathophysiological impact of such astrocytic A 2A R upsurge remains unclear.…”

mentioning

confidence: 99%

A_2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

Paiva

Carvalho

Santos

et al. 2019

Glia

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Adenosine A2A receptors (A2AR) are modulators of various physiological processes essential for brain homeostasis and fine synaptic tuning. In certain neurodegenerative conditions, notably Alzheimer's disease (AD), A2ARs are pathologically upregulated in neurons but also in astrocytes. In that context, the use of A2ARs inhibitors, normalizing impaired receptor function, is seen as a potential therapeutic strategy. However, the impact of A2AR alterations, particularly in astrocytes, is not fully understood. Here, we investigated the effect of A2AR overexpression on transcriptional deregulation in primary astrocytic cultures. By performing whole transcriptome analysis, we found that A2AR overexpression promotes robust transcriptional changes, mostly affecting immune response, angiogenesis, and cell activation‐related genes. Importantly, we observed that treatment with SCH58261, a selective A2AR antagonist, restored the expression levels of several inflammatory and astrocytic activation‐related genes, such as Interleukin‐1beta and vimentin. This supports the notion that A2AR blockade could restore some astrocytic dysfunctions associated with abnormal A2AR expression, further arguing for a potential beneficial impact of receptor antagonists in A2AR‐induced transcriptional deregulation, inflammation, and astrogliosis. Overall, our findings provide novel insights into the putative impact of A2AR overexpression on transcriptional deregulation in astrocytes, thereby opening novel avenues for the use of A2AR antagonists as potential therapeutic strategy in neurodegenerative diseases.

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Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

Cited by 50 publications

References 102 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

Adenosine A_2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons

A_2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

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Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

Cited by 50 publications

References 102 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

Adenosine A2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons

A2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

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Adenosine A_2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons

A_2AR‐induced transcriptional deregulation in astrocytes: An in vitro study