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

• Published in: Brain (London, England : 1878) Vol. 147; no. 8; pp. 2691 - 2705
• Main Authors: Gomez-Murcia, Victoria, 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-08-2024
• Series: Brain - A Journal of Neurology
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Disease Models, Animal; Hippocampus - metabolism; Hippocampus - pathology; Life Sciences; Male; Memory Disorders - genetics; Memory Disorders - metabolism; Memory Disorders - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons - metabolism; Neurons - pathology; Original; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Presenilin-1 - genetics; Receptor, Adenosine A2A - genetics; Receptor, Adenosine A2A - metabolism; Synapses - metabolism; Synapses - pathology; adenosine; A2A receptor; Alzheimer’s disease; Synapse loss; A(2A) receptor; Alzheimer's disease
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awae113

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.