Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor

Brain. 2019 Nov 1;142(11):3636-3654. doi: 10.1093/brain/awz288.


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.

Keywords: A2A receptor; C1q; adenosine; microglia; tau.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autopsy
  • Complement C1q / metabolism*
  • Frontotemporal Lobar Degeneration / genetics
  • Frontotemporal Lobar Degeneration / metabolism
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Memory Disorders / etiology
  • Memory Disorders / psychology
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neurons / metabolism*
  • Receptor, Adenosine A2A / genetics*
  • Receptor, Adenosine A2A / metabolism*
  • Spatial Learning
  • Synapses / pathology*
  • Tauopathies / genetics*
  • Tauopathies / pathology*
  • Tauopathies / psychology
  • tau Proteins / genetics


  • ADORA2A protein, human
  • Adora2a protein, mouse
  • MAPT protein, human
  • Receptor, Adenosine A2A
  • tau Proteins
  • Complement C1q