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Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.

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dc.contributor.authorLaunay, Agathe
dc.contributor.authorCarvalho, Kévin
dc.contributor.authorBurgard, Anaëlle
dc.contributor.authorMeriaux, Céline
dc.contributor.authorCaillierez, Raphaëlle
dc.contributor.authorEddarkaoui, Sabiha
dc.contributor.authorKilinc, Devrim
dc.contributor.authorSiedlecki-Wullich, Dolores
dc.contributor.authorBesegher, Mélanie
dc.contributor.authorBégard, Séverine
dc.contributor.authorThiroux, Bryan
dc.contributor.authorJung, Matthieu
dc.contributor.authorNebie, Ouada
dc.contributor.authorWisztorski, Maxence
dc.contributor.authorDéglon, Nicole
dc.contributor.authorMontmasson, Claire
dc.contributor.authorBemelmans, Alexis-Pierre
dc.contributor.authorHamdane, Malika
dc.contributor.authorLebouvier, Thibaud
dc.contributor.authorVieau, Didier
dc.contributor.authorFournier, Isabelle
dc.contributor.authorBuee, Luc
dc.contributor.authorLévi, Sabine
dc.contributor.authorLopes, Luisa V
dc.contributor.authorBoutillier, Anne-Laurence
dc.contributor.authorFaivre, Emilie
dc.contributor.authorBlum, David
dc.contributor.authorGómez Murcia, Victoria
dc.contributor.departmentFarmacología
dc.date.accessioned2026-04-15T11:52:52Z
dc.date.available2026-04-15T11:52:52Z
dc.date.copyright© The Author(s) 2024
dc.date.issued2024-08-01
dc.description.abstractEarly 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.
dc.formatapplication/pdf
dc.format.extent15
dc.identifier.citationBRAIN 2024: 147; 2691–2705
dc.identifier.other38964748
dc.identifier.urihttp://hdl.handle.net/10201/225861
dc.languageeng
dc.language.isoen
dc.relationThis work was supported by grants from Programmes d’Investissements d’Avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease). This project has been particularly supported by The Network of Centres of Excellence in Neurodegeneration (CoEN, 5008), Fédération pour la Recherche sur le Cerveau (FRC) and Agence National de la Recherche (ANR) JANUS. Our laboratories are also supported by ANR (ADORASTrAU, METABOTAU, Nintendo, Primalz, Microgliostress), Fondation pour la Recherche Médicale, Association France Alzheimer, as well as Inserm, CNRS, Université de Lille. V.G.-M. was supported by Fondation Alzheimer and Fondation pour la Recherche Médicale (SPF20160936000). A.L. is supported by Fondation pour la Recherche Médicale (ECO202106013670) and Vaincre Alzheimer (FR-24054T). Sequencing was performed by the GenomEast platform, a member of the ‘France Génomique’ consortium (ANR-10-INBS-0009).
dc.relation.publisherversionhttps://academic.oup.com/brain/article/147/8/2691/7705966
dc.rightsAttribution 4.0 International*
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectA2A receptor
dc.subjectAlzheimer’s disease
dc.subjectSynapse loss
dc.subjectAdenosine
dc.subject.odsObjetivo 3: Salud
dc.titleNeuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
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relation.isAuthorOfPublication5d90b1d7-e72c-4772-b056-021f2ac2f63c
relation.isAuthorOfPublication.latestForDiscovery5d90b1d7-e72c-4772-b056-021f2ac2f63c
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