Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice
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| Titel: | Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice |
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| Autoren: | Victoria Gomez-Murcia, Agathe Launay, Kévin Carvalho, Anaëlle Burgard, Céline Meriaux, Raphaëlle Caillierez, Sabiha Eddarkaoui, Devrim Kilinc, Dolores Siedlecki-Wullich, Mélanie Besegher, Séverine Bégard, Bryan Thiroux, Matthieu Jung, Ouada Nebie, Maxence Wisztorski, Nicole Déglon, Claire Montmasson, Alexis-Pierre Bemelmans, Malika Hamdane, Thibaud Lebouvier, Didier Vieau, Isabelle Fournier, Luc Buee, Sabine Lévi, Luisa V Lopes, Anne-Laurence Boutillier, Emilie Faivre, David Blum |
| Weitere Verfasser: | Université de Lille, LillOA, Anne Laurence, Boutillier |
| Quelle: | Brain Brain, vol. 147, no. 8, pp. 2691-2705 |
| Verlagsinformationen: | Oxford University Press (OUP), 2024. |
| Publikationsjahr: | 2024 |
| Schlagwörter: | Male, 0301 basic medicine, Receptor, Adenosine A2A, Mice, Transgenic, Plaque, Amyloid, A(2A) receptor, Hippocampus, Animals, Memory Disorders/metabolism, Memory Disorders/genetics, Memory Disorders/pathology, Mice, Receptor, Adenosine A2A/metabolism, Receptor, Adenosine A2A/genetics, Synapses/metabolism, Synapses/pathology, Amyloid beta-Protein Precursor/genetics, Amyloid beta-Protein Precursor/metabolism, Neurons/metabolism, Neurons/pathology, Alzheimer Disease/metabolism, Alzheimer Disease/pathology, Alzheimer Disease/genetics, Hippocampus/metabolism, Hippocampus/pathology, Presenilin-1/genetics, Disease Models, Animal, Plaque, Amyloid/pathology, Plaque, Amyloid/metabolism, Mice, Inbred C57BL, A2A receptor, Alzheimer's disease, Synapse loss, adenosine, Amyloid beta-Protein Precursor, 03 medical and health sciences, Alzheimer Disease, Presenilin-1, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurons, Memory Disorders, 0303 health sciences, 3. Good health, [SDV] Life Sciences [q-bio], Synapses, Original Article |
| Beschreibung: | 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. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awae113 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/38964748 https://hal.univ-lille.fr/hal-04684882v1/document https://hal.univ-lille.fr/hal-04684882v1 https://doi.org/10.1093/brain/awae113 https://serval.unil.ch/resource/serval:BIB_58B757DC2950.P001/REF.pdf https://serval.unil.ch/notice/serval:BIB_58B757DC2950 http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_58B757DC29503 |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Dokumentencode: | edsair.doi.dedup.....8c7de80cd8b6f88427f4f4857a4c3b16 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | 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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| ISSN: | 14602156 00068950 |
| DOI: | 10.1093/brain/awae113 |