L. F. Abbott and W. G. Regehr, Synaptic computation, Nature, vol.431, pp.796-803, 2004.

G. W. Arendash, T. Mori, C. Cao, M. Mamcarz, M. Runfeldt et al., Caffeine reverses cognitive impairment and decreases brain amyloid-? levels in aged Alzheimer's disease mice, J. Alzheimers Dis, vol.17, pp.661-680, 2009.

G. W. Arendash, W. Schleif, K. Rezai-zadeh, E. K. Jackson, L. C. Zacharia et al., Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain-amyloid production, Neuroscience, vol.142, pp.941-952, 2006.

R. Baeta-corral, B. Johansson, and L. Giménez-llort, Long-term treatment with low-dose caffeine worsens BPSD-like profile in 3xTg-AD mice model of Alzheimer's disease and affects mice with normal aging, Front. Pharmacol, vol.9, p.79, 2018.

V. L. Batalha, D. G. Ferreira, J. E. Coelho, J. S. Valadas, R. Gomes et al., The caffeine-binding adenosine A 2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function, Sci. Rep, vol.6, p.31493, 2016.
URL : https://hal.archives-ouvertes.fr/inserm-01833352

V. L. Batalha, J. M. Pego, B. M. Fontinha, A. R. Costenla, J. S. Valadas et al., Adenosine A 2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation, Mol. Psychiatry, vol.18, pp.320-331, 2013.

D. Blum, M. Galas, A. Pintor, E. Brouillet, C. Ledent et al., A dual role of adenosine A 2A receptors in 3-nitropropionic acid-induced striatal lesions: implications for the neuroprotective potential of A 2A antagonists, J. Neurosci, vol.23, pp.5361-5369, 2003.

D. Blum, R. Hourez, M. Galas, P. Popoli, and S. N. Schiffmann, Adenosine receptors and Huntington's disease: implications for pathogenesis and therapeutics, Lancet Neurol, vol.2, pp.411-414, 2003.

L. Bulavina, F. Szulzewsky, A. Rocha, G. Krabbe, S. C. Robson et al., NTPDase1 activity attenuates microglial phagocytosis, Purinergic Signal, vol.9, pp.199-205, 2013.

P. M. Canas, L. O. Porciuncula, G. M. Cunha, C. G. Silva, N. J. Machado et al., Adenosine A 2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by ?-amyloid peptides via p38 mitogen-activated protein kinase pathway, J. Neurosci, vol.29, pp.14741-14751, 2009.

C. Cao, J. R. Cirrito, X. Lin, L. Wang, D. K. Verges et al., Caffeine suppresses amyloid-? levels in plasma and brain of Alzheimer's disease transgenic mice, J. Alzheimers Dis, vol.17, pp.681-697, 2009.

C. M. Carr, R. , and J. , At the junction of SNARE and SM protein function, Curr. Opin. Cell Biol, vol.22, pp.519-527, 2010.

L. E. Collins, D. J. Galtieri, L. T. Brennum, T. N. Sager, J. Hockemeyer et al., Oral tremor induced by the muscarinic agonist pilocarpine is suppressed by the adenosine A 2A antagonists MSX-3 and SCH58261, but not the adenosine A 1 antagonist DPCPX, Pharmacol. Biochem. Behav, vol.94, pp.561-569, 2010.

S. Cristóvão-ferreira, G. Navarro, M. Brugarolas, K. Pérez-capote, S. H. Vaz et al., A1R-A 2A R heteromers coupled to Gsand Gi/0proteins modulate GABA transport into astrocytes, Purinergic Signal, vol.9, pp.433-449, 2013.

R. A. Cunha, How does adenosine control neuronal dysfunction and neurodegeneration?, J. Neurochem, vol.139, pp.1019-1055, 2016.

E. Cuyvers and K. Sleegers, Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond, Lancet Neurol, vol.15, pp.857-868, 2016.

O. P. Dall'lgna, P. Fett, M. W. Gomes, D. O. Souza, R. A. Cunha et al., Caffeine and adenosine A 2A receptor antagonists prevent ?-amyloid (25-35)-induced cognitive deficits in mice, Exp. Neurol, vol.203, pp.241-245, 2007.

O. P. Dall'lgna, L. O. Porciúncula, D. O. Souza, R. A. Cunha, L. et al., Neuroprotection by caffeine and adenosine A 2A receptor blockade of ?-amyloid neurotoxicity, Br. J. Pharmacol, vol.138, pp.1207-1209, 2003.

C. Duyckaerts, H. Braak, J. Brion, L. Buée, K. Del-tredici et al., PART is part of Alzheimer disease, Acta Neuropathol, vol.129, pp.749-756, 2015.

V. Flaten, C. Laurent, J. E. Coelho, U. Sandau, V. L. Batalha et al., From epidemiology to pathophysiology: what about caffeine in Alzheimer's disease?, Biochem. Soc. Trans, vol.42, pp.587-592, 2014.

M. Garcia-alloza, E. M. Robbins, S. X. Zhang-nunes, S. M. Purcell, R. A. Betensky et al., Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease, Neurobiol. Dis, vol.24, pp.516-524, 2006.

O. Genc, O. Kochubey, R. F. Toonen, M. Verhage, and R. Schneggenburger, Munc18-1 is a dynamically regulated PKC target during short-term enhancement of transmitter release, Elife, vol.3, p.1715, 2014.

L. Giménez-llort, S. N. Schiffmann, T. Shmidt, L. Canela, L. Camón et al., Working memory deficits in transgenic rats overexpressing human adenosine A 2A receptors in the brain, Neurobiol. Learn. Mem, vol.87, pp.42-56, 2007.

S. Gyoneva, L. Shapiro, C. Lazo, E. Garnier-amblard, Y. Smith et al., Adenosine A 2A receptor antagonism reverses inflammationinduced impairment of microglial process extension in a model of Parkinson's disease, Neurobiol. Dis, vol.67, pp.191-202, 2014.

S. Gyoneva, S. A. Swanger, J. Zhang, D. Weinshenker, and S. F. Traynelis, Altered motility of plaque-associated microglia in a model of Alzheimer's disease, Neuroscience, vol.330, pp.410-420, 2016.

M. T. Heneka, M. J. Carson, J. Khoury, G. E. Landreth, F. Brosseron et al., Neuroinflammation in Alzheimer's disease, Lancet Neurol, vol.14, pp.70016-70021, 2015.

E. Horgusluoglu-moloch, K. Nho, S. L. Risacher, S. Kim, T. Foroud et al., Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease, Neurobiol. Aging, vol.60, pp.92-103, 2017.

J. L. Jankowsky, H. H. Slunt, T. Ratovitski, N. A. Jenkins, N. G. Copeland et al., Co-expression of multiple transgenes in mouse CNS: a comparison of strategies, Biomol. Eng, vol.17, pp.67-70, 2001.

M. P. Kaster, N. J. Machado, H. B. Silva, A. Nunes, A. P. Ardais et al., Caffeine acts through neuronal adenosine A 2A receptors to prevent mood and memory dysfunction triggered by chronic stress, Proc. Natl. Acad. Sci. U S A, vol.112, pp.7833-7838, 2015.

T. Kim, J. Lee, S. Park, K. Lee, J. Seo et al., Analysis of differential plaque depositions in the brains of Tg2576 and TgAPPswe/PS1dE9 transgenic mouse models of Alzheimer disease, Exp. Mol. Med, vol.44, pp.492-502, 2012.

G. Krabbe, A. Halle, V. Matyash, J. L. Rinnenthal, G. D. Eom et al., Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology, PLoS One, vol.8, p.60921, 2013.

C. Laurent, L. Buée, and D. Blum, Tau and neuroinflammation: what impact for Alzheimer's disease and tauopathies?, Biomed. J, vol.41, pp.21-33, 2018.

C. Laurent, S. Burnouf, B. Ferry, V. L. Batalha, J. E. Coelho et al., , 2016.

, A 2A adenosine receptor deletion is protective in a mouse model of Tauopathy, Mol. Psychiatry, vol.21, pp.97-107

C. Laurent, S. Eddarkaoui, M. Derisbourg, A. Leboucher, D. Demeyer et al., Beneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology, Neurobiol. Aging, vol.35, pp.2079-2090, 2014.

L. Guennec, K. Veugelen, S. Quenez, O. Szaruga, M. Rousseau et al., Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset alzheimer disease generates longer amyloid seeds, Neurobiol. Dis, vol.104, pp.97-103, 2017.

C. Lee, C. Chang, C. Lin, H. Lai, Y. Kao et al., Adenosine augmentation evoked by an ENT1 inhibitor improves memory impairment and neuronal plasticity in the APP/PS1 mouse model of Alzheimer's disease, Mol. Neurobiol, 2018.
URL : https://hal.archives-ouvertes.fr/inserm-01833298

P. Li, D. Rial, P. M. Canas, J. Yoo, W. Li et al., Optogenetic activation of intracellular adenosine A 2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory, Mol. Psychiatry, vol.20, pp.1339-1349, 2015.

L. V. Lopes, R. A. Cunha, and J. A. Ribeiro, Increase in the number, G protein coupling and efficiency of facilitatory adenosine A 2A receptors in the limbic cortex, but not striatum, of aged rats, J. Neurochem, vol.73, pp.1733-1738, 1999.

J. Lu, J. Cui, X. Li, X. Wang, Y. Zhou et al., An AntiParkinson's disease drug via targeting adenosine A 2A receptor enhances amyloid-? generation and ?-secretase activity, PLoS One, vol.11, 2016.

N. J. Machado, A. P. Simões, H. B. Silva, A. P. Ardais, M. P. Kaster et al., Caffeine reverts memory but not mood impairment in a depression-prone mouse strain with up-regulated adenosine A 2A receptor in hippocampal glutamate synapses, Mol. Neurobiol, vol.54, pp.1552-1563, 2017.

E. Marciniak, E. Faivre, P. Dutar, C. Alves-pires, D. Demeyer et al., The Chemokine MIP-1?/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory, Sci. Rep, vol.5, p.15862, 2015.

C. L. Masters, G. Simms, N. A. Weinman, G. Multhaup, B. L. Mcdonald et al., Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proc. Natl. Acad. Sci. U S A, vol.82, pp.4245-4249, 1985.

M. Matos, E. Augusto, A. D. Santos-rodrigues, M. A. Schwarzschild, J. Chen et al., Adenosine A 2A receptors modulate glutamate uptake in cultured astrocytes and gliosomes, Glia, vol.60, pp.702-716, 2012.

M. Matos, H. Y. Shen, E. Augusto, Y. Wang, C. J. Wei et al., Deletion of adenosine A 2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia, Biol. Psychiatry, vol.78, pp.763-774, 2015.

B. V. Nagpure and J. S. Bian, Hydrogen sulfide inhibits A 2A adenosine receptor agonist induced ?-amyloid production in SH-SY5Y neuroblastoma cells via a cAMP dependent pathway, PLoS One, vol.9, p.88508, 2014.
DOI : 10.1371/journal.pone.0088508

URL : https://doi.org/10.1371/journal.pone.0088508

T. Nishizaki, K. Nagai, T. Nomura, H. Tada, T. Kanno et al., A new neuromodulatory pathway with a glial contribution mediated via A 2A adenosine receptors, Glia, vol.39, pp.133-147, 2002.
DOI : 10.1002/glia.10100

A. G. Orr, A. L. Orr, X. J. Li, R. E. Gross, and S. F. Traynelis, , 2009.

, Adenosine A 2A receptor mediates microglial process retraction, Nat. Neurosci, vol.12, pp.872-878

A. G. Orr, E. C. Hsiao, M. M. Wang, K. Ho, D. H. Kim et al., Astrocytic adenosine receptor A 2A and G s-coupled signaling regulate memory, Nat. Neurosci, vol.18, pp.423-434, 2015.

A. G. Orr, I. Lo, H. Schumacher, K. Ho, M. Gill et al., Istradefylline reduces memory deficits in aging mice with amyloid pathology, Neurobiol. Dis, vol.110, pp.29-36, 2018.

J. Puoliväli, J. Wang, T. Heikkinen, M. Heikkilä, T. Tapiola et al., Hippocampal Abeta42 levels correlate with spatial memory deficit in APP and PS1 double transgenic mice, Neurobiol. Dis, vol.9, pp.339-347, 2002.

N. Rebola, A. M. Sebastião, A. De-mendonca, C. R. Oliveira, J. A. Ribeiro et al., Enhanced adenosine A 2A receptor facilitation of synaptic transmission in the hippocampus of aged rats, J. Neurophysiol, vol.90, pp.1295-1303, 2003.

N. Rebola, A. P. Simões, P. M. Canas, A. R. Tomé, G. M. Andrade et al., Adenosine A 2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction, J. Neurochem, vol.117, pp.100-111, 2011.

C. Reitz, C. Brayne, and R. Mayeux, Epidemiology of Alzheimer disease, Nat. Rev. Neurol, vol.7, pp.137-152, 2011.

R. T. Sasmono, D. Oceandy, J. W. Pollard, W. Tong, P. Pavli et al., A macrophage colony-stimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse, Blood, vol.101, pp.1155-1163, 2003.

R. Sauer, J. Maurinsh, U. Reith, F. Fülle, K. N. Klotz et al., Water-soluble phosphate prodrugs of 1-propargyl-8-styrylxanthine derivatives, A 2A-selective adenosine receptor antagonists, J. Med. Chem, vol.43, pp.440-448, 2000.

J. C. Savage, T. Jay, E. Goduni, C. Quigley, M. M. Mariani et al., Nuclear receptors license phagocytosis by trem2 + myeloid cells in mouse models of Alzheimer's disease, J. Neurosci, vol.35, pp.6532-6543, 2015.

A. Savonenko, G. M. Xu, T. Melnikova, J. L. Morton, V. Gonzales et al., Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to ?-amyloid deposition and neurotransmitter abnormalities, Neurobiol. Dis, vol.18, pp.602-617, 2005.

A. C. Silva, C. Lemos, F. Q. Gonçalves, A. V. Pliássova, N. J. Machado et al., Blockade of adenosine A 2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer's disease, Neurobiol Dis, vol.31, pp.72-81, 2018.

E. Sipos, A. Kurunczi, Á. Kasza, J. Horváth, K. Felszeghy et al., ?-Amyloid pathology in the entorhinal cortex of rats induces memory deficits: implications for Alzheimer's disease, Neuroscience, vol.147, pp.28-36, 2007.

S. W. Snyder, U. S. Ladror, W. S. Wade, G. T. Wang, L. W. Barrett et al., Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths, Biophys. J, vol.67, pp.1216-1228, 1994.

Y. Suh, C. , and F. , Amyloid precursor protein, presenilins, and alpha synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease, Pharmacol. Rev, vol.54, pp.469-525, 2002.

M. Temido-ferreira, D. G. Ferreira, V. L. Batalha, I. Marques-morgado, J. E. Coelho et al., Age-related shift in LTD is dependent on neuronal adenosine A 2A receptors interplay with mGluR5 and NMDA receptors, Mol. Psychiatry, 2018.

R. F. Toonen and M. Verhage, Munc18-1 in secretion: lonely Munc joins SNARE team and takes control, Trends Neurosci, vol.30, pp.564-572, 2007.

S. Viana-da-silva, M. G. Haberl, P. Zhang, P. Bethge, C. Lemos et al., Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A 2A receptors, Nat. Commun, vol.7, p.11915, 2016.

L. Yu, J. E. Coelho, X. Zhang, Y. Fu, A. Tillman et al., Uncovering multiple molecular targets for caffeine using a drug target validation strategy combining A 2A receptor knockout mice with microarray profiling, Physiol. Genomics, vol.37, pp.199-210, 2008.

W. Zhang, J. Hao, R. Liu, Z. Zhang, G. Lei et al., Soluble A? levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease, Behav. Brain Res, vol.222, pp.342-350, 2011.

Z. A. Zhao, Y. Zhao, Y. L. Ning, N. Yang, Y. Peng et al., Adenosine A 2A receptor inactivation alleviates early-onset cognitive dysfunction after traumatic brain injury involving an inhibition of tau hyperphosphorylation, Transl. Psychiatry, vol.7, p.1123, 2017.

, Conflict of Interest Statement: The authors declare that the research was

. Copyright-©-;-faivre, . Coelho, . Zornbach, . Malik, . Baqi et al., This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, 2018.