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Gómez Murcia, Victoria

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Gómez Murcia, Victoria
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Universidad de Murcia. Departamento de Farmacología
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    Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.
    (2024-08-01) Launay, Agathe; Carvalho, Kévin; Burgard, Anaëlle; Meriaux, Céline; Caillierez, Raphaëlle; Eddarkaoui, Sabiha; Kilinc, Devrim; Siedlecki-Wullich, Dolores; Besegher, Mélanie; Bégard, Séverine; Thiroux, Bryan; Jung, Matthieu; Nebie, Ouada; Wisztorski, Maxence; Déglon, Nicole; Montmasson, Claire; Bemelmans, Alexis-Pierre; Hamdane, Malika; Lebouvier, Thibaud; Vieau, Didier; Fournier, Isabelle; Buee, Luc; Lévi, Sabine; Lopes, Luisa V; Boutillier, Anne-Laurence; Faivre, Emilie; Blum, David; Gómez Murcia, Victoria; Farmacología
    Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder.
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    Upregulation of adenosine A2A receptor in astrocytes is sufficient to trigger hippocampal multicellular dysfunctions and memory deficits.
    (2024) Launay, Agathe; Carvalho, Kevin; Genin, Athenais; Gauvrit, Thibaut; Nobili, Paola; Augustin, Emma; Burgard, Anaëlle; Gambi, Johanne; Fourmy, Deborah; Thiroux, Bryan; Vieau, Didier; Bemelmans, Alexis-Pierre; Le Gras, Stephanie; Buee, Luc; Orr, Miranda E; Audinat, Etienne; Boutillier, Anne-Laurence; Bonvento, Gilles; Cambon, Karine; Faivre, Emilie; Blum, David; Gómez Murcia, Victoria; Farmacología
    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 A (AR) and A (AR) receptors. Interestingly, AR 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 AR in astrocytes remain poorly understood. In the present study, we induced the upregulation of AR in hippocampal astrocytes using dedicated AAVs and comprehensively evaluated the functional consequences in 4 months-old C57Bl6/J mice. Our results show that AR 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 AR upregulation in hippocampal astrocytes were sufficient to induce impairments of short-term spatial memory and spatial learning. This study highlights the impact of astrocytic AR 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.
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