Author(s):
Carvalho, Kevin ; Faivre, Emilie ; Pietrowski, Marie J. ; Marques, Xavier ; Gomez-Murcia, Victoria ; Deleau, Aude ; Huin, Vincent ; Hansen, Jan N ; Kozlov, Stanislav ; Danis, Clément ; Temido Ferreira, Mariana ; Coelho, Joana E ; Mériaux, Céline ; Eddarkaoui, Sabiha ; Gras, Stéphanie Le ; Dumoulin, Mélanie ; Cellai, Lucrezia ; Landrieu, Isabelle ; Chern, Yijuang ; Hamdane, Malika ; Buée, Luc ; Boutillier, Anne-Laurence ; Levi, Sabine ; Halle, Annett ; Lopes, Luisa V. ; Blum, David
Date: 2019
Persistent ID: http://hdl.handle.net/10451/55392
Origin: Repositório da Universidade de Lisboa
Subject(s): A2A receptor; C1q; Adenosine; Microglia; Tau
Description
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.
