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000144978 0247_ $$2doi$$a10.1093/brain/awz288
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000144978 041__ $$aEnglish
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000144978 1001_ $$aCarvalho, Kevin$$b0
000144978 245__ $$aExacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor.
000144978 260__ $$aOxford$$bOxford Univ. Press$$c2019
000144978 264_1 $$2Crossref$$3online$$bOxford University Press (OUP)$$c2019-10-10
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000144978 520__ $$aAccumulating data support the role of tau pathology in cognitive decline in ageing and Alzheimer's disease, but underlying mechanisms remain ill-defined. Interestingly, ageing and Alzheimer's disease have been associated with an abnormal upregulation of adenosine A2A receptor (A2AR), a fine tuner of synaptic plasticity. However, the link between A2AR signalling and tau pathology has remained largely unexplored. In the present study, we report for the first time a significant upregulation of A2AR in patients suffering from frontotemporal lobar degeneration with the MAPT P301L mutation. To model these alterations, we induced neuronal A2AR upregulation in a tauopathy mouse model (THY-Tau22) using a new conditional strain allowing forebrain overexpression of the receptor. We found that neuronal A2AR upregulation increases tau hyperphosphorylation, potentiating the onset of tau-induced memory deficits. This detrimental effect was linked to a singular microglial signature as revealed by RNA sequencing analysis. In particular, we found that A2AR overexpression in THY-Tau22 mice led to the hippocampal upregulation of C1q complement protein-also observed in patients with frontotemporal lobar degeneration-and correlated with the loss of glutamatergic synapses, likely underlying the observed memory deficits. These data reveal a key impact of overactive neuronal A2AR in the onset of synaptic loss in tauopathies, paving the way for new therapeutic approaches.
000144978 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000144978 542__ $$2Crossref$$i2019-10-10$$uhttp://creativecommons.org/licenses/by-nc/4.0/
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000144978 650_7 $$2NLM Chemicals$$aADORA2A protein, human
000144978 650_7 $$2NLM Chemicals$$aAdora2a protein, mouse
000144978 650_7 $$2NLM Chemicals$$aMAPT protein, human
000144978 650_7 $$2NLM Chemicals$$aReceptor, Adenosine A2A
000144978 650_7 $$2NLM Chemicals$$atau Proteins
000144978 650_7 $$080295-33-6$$2NLM Chemicals$$aComplement C1q
000144978 650_2 $$2MeSH$$aAnimals
000144978 650_2 $$2MeSH$$aAutopsy
000144978 650_2 $$2MeSH$$aComplement C1q: metabolism
000144978 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: genetics
000144978 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: metabolism
000144978 650_2 $$2MeSH$$aHippocampus: metabolism
000144978 650_2 $$2MeSH$$aHippocampus: pathology
000144978 650_2 $$2MeSH$$aHumans
000144978 650_2 $$2MeSH$$aMemory Disorders: etiology
000144978 650_2 $$2MeSH$$aMemory Disorders: psychology
000144978 650_2 $$2MeSH$$aMice
000144978 650_2 $$2MeSH$$aMice, Transgenic
000144978 650_2 $$2MeSH$$aMutation
000144978 650_2 $$2MeSH$$aNeurons: metabolism
000144978 650_2 $$2MeSH$$aReceptor, Adenosine A2A: genetics
000144978 650_2 $$2MeSH$$aReceptor, Adenosine A2A: metabolism
000144978 650_2 $$2MeSH$$aSpatial Learning
000144978 650_2 $$2MeSH$$aSynapses: pathology
000144978 650_2 $$2MeSH$$aTauopathies: genetics
000144978 650_2 $$2MeSH$$aTauopathies: pathology
000144978 650_2 $$2MeSH$$aTauopathies: psychology
000144978 650_2 $$2MeSH$$atau Proteins: genetics
000144978 7001_ $$aFaivre, Emilie$$b1
000144978 7001_ $$0P:(DE-2719)2812560$$aPietrowski, Marie J$$b2$$udzne
000144978 7001_ $$aMarques, Xavier$$b3
000144978 7001_ $$aGomez-Murcia, Victoria$$b4
000144978 7001_ $$aDeleau, Aude$$b5
000144978 7001_ $$aHuin, Vincent$$b6
000144978 7001_ $$0P:(DE-2719)2812073$$aHansen, Jan N$$b7$$udzne
000144978 7001_ $$0P:(DE-2719)2812648$$aKozlov, Stanislav$$b8$$udzne
000144978 7001_ $$aDanis, Clément$$b9
000144978 7001_ $$aTemido-Ferreira, Mariana$$b10
000144978 7001_ $$aCoelho, Joana E$$b11
000144978 7001_ $$aMériaux, Céline$$b12
000144978 7001_ $$aEddarkaoui, Sabiha$$b13
000144978 7001_ $$aGras, Stéphanie Le$$b14
000144978 7001_ $$aDumoulin, Mélanie$$b15
000144978 7001_ $$aCellai, Lucrezia$$b16
000144978 7001_ $$aBank, NeuroCEB Brain$$b17$$eCollaboration Author
000144978 7001_ $$aLandrieu, Isabelle$$b18
000144978 7001_ $$aChern, Yijuang$$b19
000144978 7001_ $$aHamdane, Malika$$b20
000144978 7001_ $$aBuée, Luc$$b21
000144978 7001_ $$aBoutillier, Anne-Laurence$$b22
000144978 7001_ $$aLevi, Sabine$$b23
000144978 7001_ $$0P:(DE-2719)2812038$$aHalle, Annett$$b24$$udzne
000144978 7001_ $$aLopes, Luisa V$$b25
000144978 7001_ $$0P:(DE-HGF)0$$aBlum, David$$b26$$eCorresponding author
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