%0 Journal Article
%A Carvalho, Kevin
%A Faivre, Emilie
%A Pietrowski, Marie J
%A Marques, Xavier
%A Gomez-Murcia, Victoria
%A Deleau, Aude
%A Huin, Vincent
%A Hansen, Jan N
%A Kozlov, Stanislav
%A Danis, Clément
%A Temido-Ferreira, Mariana
%A Coelho, Joana E
%A Mériaux, Céline
%A Eddarkaoui, Sabiha
%A Gras, Stéphanie Le
%A Dumoulin, Mélanie
%A Cellai, Lucrezia
%A Landrieu, Isabelle
%A Chern, Yijuang
%A Hamdane, Malika
%A Buée, Luc
%A Boutillier, Anne-Laurence
%A Levi, Sabine
%A Halle, Annett
%A Lopes, Luisa V
%A Blum, David
%T Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor.
%J Brain
%V 142
%N 11
%@ 0006-8950
%C Oxford
%I Oxford Univ. Press
%M DZNE-2020-00342
%P 3636-3654
%D 2019
%X Accumulating 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.
%K Animals
%K Autopsy
%K Complement C1q: metabolism
%K Frontotemporal Lobar Degeneration: genetics
%K Frontotemporal Lobar Degeneration: metabolism
%K Hippocampus: metabolism
%K Hippocampus: pathology
%K Humans
%K Memory Disorders: etiology
%K Memory Disorders: psychology
%K Mice
%K Mice, Transgenic
%K Mutation
%K Neurons: metabolism
%K Receptor, Adenosine A2A: genetics
%K Receptor, Adenosine A2A: metabolism
%K Spatial Learning
%K Synapses: pathology
%K Tauopathies: genetics
%K Tauopathies: pathology
%K Tauopathies: psychology
%K tau Proteins: genetics
%K ADORA2A protein, human (NLM Chemicals)
%K Adora2a protein, mouse (NLM Chemicals)
%K MAPT protein, human (NLM Chemicals)
%K Receptor, Adenosine A2A (NLM Chemicals)
%K tau Proteins (NLM Chemicals)
%K Complement C1q (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:31599329
%2 pmc:PMC6821333
%R 10.1093/brain/awz288
%U https://pub.dzne.de/record/144978