TY  - JOUR
AU  - Carvalho, Kevin
AU  - Faivre, Emilie
AU  - Pietrowski, Marie J
AU  - Marques, Xavier
AU  - Gomez-Murcia, Victoria
AU  - Deleau, Aude
AU  - Huin, Vincent
AU  - Hansen, Jan N
AU  - Kozlov, Stanislav
AU  - Danis, Clément
AU  - Temido-Ferreira, Mariana
AU  - Coelho, Joana E
AU  - Mériaux, Céline
AU  - Eddarkaoui, Sabiha
AU  - Gras, Stéphanie Le
AU  - Dumoulin, Mélanie
AU  - Cellai, Lucrezia
AU  - Landrieu, Isabelle
AU  - Chern, Yijuang
AU  - Hamdane, Malika
AU  - Buée, Luc
AU  - Boutillier, Anne-Laurence
AU  - Levi, Sabine
AU  - Halle, Annett
AU  - Lopes, Luisa V
AU  - Blum, David
TI  - Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor.
JO  - Brain
VL  - 142
IS  - 11
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2020-00342
SP  - 3636-3654
PY  - 2019
AB  - 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.
KW  - Animals
KW  - Autopsy
KW  - Complement C1q: metabolism
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Hippocampus: metabolism
KW  - Hippocampus: pathology
KW  - Humans
KW  - Memory Disorders: etiology
KW  - Memory Disorders: psychology
KW  - Mice
KW  - Mice, Transgenic
KW  - Mutation
KW  - Neurons: metabolism
KW  - Receptor, Adenosine A2A: genetics
KW  - Receptor, Adenosine A2A: metabolism
KW  - Spatial Learning
KW  - Synapses: pathology
KW  - Tauopathies: genetics
KW  - Tauopathies: pathology
KW  - Tauopathies: psychology
KW  - tau Proteins: genetics
KW  - ADORA2A protein, human (NLM Chemicals)
KW  - Adora2a protein, mouse (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Receptor, Adenosine A2A (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - Complement C1q (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:31599329
C2  - pmc:PMC6821333
DO  - DOI:10.1093/brain/awz288
UR  - https://pub.dzne.de/record/144978
ER  -