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Upregulation of adenosine A2A receptor by astrocytes is sufficient to trigger hippocampal multicellular dysfunctions and memory deficits

ABSTRACT: Upregulation of adenosine A2A receptor by astrocytes is sufficient to trigger hippocampal multicellular dysfunctions and memory deficits

PROVIDER: PRJNA1135951 | ENA |

REPOSITORIES: ENA

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Upregulation of adenosine A2A receptor by astrocytes is sufficient to trigger hippocampal multicellular dysfunctions and memory deficits

Project description:Adenosine is an ubiquitous neuromodulator that ensures cerebral homeostasis. It exerts numerous functions through the activation of G-protein-coupled adenosine receptors (ARs), in particular A1 (A1R) and A2A (A2AR) receptors. Interestingly, A2AR levels are upregulated in cortical and hippocampal regions in several pathological conditions such as Alzheimer's disease, tauopathies or epilepsia. Such abnormal upregulations have been particularly reported in astrocytes, glial cells that play a key role in regulating synaptic plasticity. However, the overall impact and the underlying mechanisms associated with increased A2AR in astrocytes remain poorly understood. In the present study, we induced the upregulation of A2AR in hippocampal astrocytes using dedicated AAVs and comprehensively evaluated the functional consequences in 4 months-old C57Bl6/J mice. Our results show that A2AR upregulation primarily promotes alterations of astrocyte reactivity, morphology and transcriptome, with a link to aging-like phenotype as well as secondary impairments of neuronal excitability and microglial phenotype. These changes driven by a restricted A2AR upregulation in hippocampal astrocytes were sufficient to induce impairments of short-term spatial memory and spatial learning. This study highlights the impact of astrocytic A2AR upregulation, as seen in various neurological conditions, on the development of a detrimental multicellular response associated with memory alterations and provides an additional proof-of-concept for the value of targeting this receptor in different neurodegenerative conditions.

2025-08-22 | GSE272248 | GEO

Gene expression profile in the heart of wild type and Adenosine Receptor A2a over expressing mice

Project description:Adenosine binds to 4 G protein-coupled receptors located on the cardiomyocyte (A1-R, A2a-R, A2b-R and A3-R) and modulates cardiac function during both ischemia and load-induced stress. While the role of adenosine receptor-subtypes has been well defined in the setting of ischemia-reperfusion, far less is known regarding their roles in protecting the heart during other forms of cardiac stress. We characterized the gene expression profiles of heart from A2a-R over-expressing mice subjected to transverse aortic constriction to study the potential of A2a-R activation to protect from pressure-induced heart failure.

2015-03-22 | GSE45423 | GEO

Differential gene expression in activated microglia treated with adenosine A2A antagonists and A3 receptor agonists. A transcriptomics study.

Project description:Microglial activation often accompanies the plastic changes occurring in the brain of patients with neurodegenerative diseases. A2A and A3 adenosine receptors have been proposed as therapeutic targets to combat neurodegeneration. RNAseq was performed using samples isolated from lipopolysaccharide/interferon-γ activated microglia treated with SCH 58261, a selective A2A receptor antagonist and 2-Cl-IB-MECA, a selective A3 receptor agonist.

2023-10-04 | GSE222696 | GEO

Microarray analysis of a multiple myeloma cell line, MM1S, treated with adenosine A2A and Beta-2 Adrenergic Receptor agonists in combination with dexamethasone

Project description:We have used an agnostic approach to identify drug combinations by using combination high throughput screening (cHTS) technology and make the surprising discovery that adenosine A2A and beta-2 adrenergic receptor agonists are highly synergistic, selective and novel agents that enhance glucocorticoid activity in B-cell malignancies. We used the microarray study to understand the synergistic mechanism between dexamethasone and A2A receptor agonist or Beta-2 Adrenergic receptor agonist in a multiple myeloma cell line, MM1S. MM1S cells were treated with CGS-21680 or Salmeterol alone, or in combination with dexamethasone for six hours for RNA extraction and hybridization on Affymetrix microarrays.

2012-03-31 | E-GEOD-30644 | biostudies-arrayexpress

Microarray analysis of a multiple myeloma cell line, MM1S, treated with adenosine A2A and Beta-2 Adrenergic Receptor agonists in combination with dexamethasone

2012-04-01 | GSE30644 | GEO

Adenosine A2A Receptor Null Chondrocyte Transcriptome Resembles that of Human Osteoarthiris Chodnrocytes

Project description:Adenosine A2A Receptor Null Chondrocyte Transcriptome Resembles that of Human Osteoarthiris Chodnrocytes

| PRJNA610223 | ENA

Remdesivir has previously unknown anti-viral immunomodulatory properties through the Adenosine A2A Receptor pathway

Project description:The COVID-19 pandemic has unveiled an urgent need for new anti-virals to control emerging infectious diseases and potential future pandemics. Classic anti-virals are currently designed to directly interfere with pathogens. However, anti-virals are often insufficient to rapidly clear infections in the absence of an effective immune response. Immunotherapy could complement the use of anti-virals, however its application to infectious diseases remains largely unexplored. In this work, we found that the anti-viral drug remdesivir has previously unknown immunomodulatory properties which contribute to its therapeutic effect against SARS-CoV-2. These properties are due to remdesivir metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist, a function that is distinct from its intrinsic anti-viral activity. Our findings support a new rationale for the design of next-generation anti-viral agents with dual – immunomodulatory and intrinsic - anti-viral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.

2024-09-11 | GSE236563 | GEO

Remdesivir has previously unknown anti-viral immunomodulatory properties through the Adenosine A2A Receptor pathway

Project description:Remdesivir has previously unknown anti-viral immunomodulatory properties through the Adenosine A2A Receptor pathway

| PRJNA991577 | ENA

Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory.

Project description:Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.

| S-EPMC4539301 | biostudies-literature

Differential gene expression in activated microglia treated with adenosine A2A antagonists and A3 receptor agonists. A transcriptomics study.

Project description:Differential gene expression in activated microglia treated with adenosine A2A antagonists and A3 receptor agonists. A transcriptomics study.

| PRJNA923028 | ENA

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