Journal Article

DZNE-2020-00342

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor.

Carvalho, K. ; Faivre, E. ; Pietrowski, M. J.DZNE* ; Marques, X. ; Gomez-Murcia, V. ; Deleau, A. ; Huin, V. ; Hansen, J. N.DZNE* ; Kozlov, S.DZNE* ; Danis, C. ; Temido-Ferreira, M. ; Coelho, J. E. ; Mériaux, C. ; Eddarkaoui, S. ; Gras, S. L. ; Dumoulin, M. ; Cellai, L. ; Bank, N. B. (Collaboration Author) ; Landrieu, I. ; Chern, Y. ; Hamdane, M. ; Buée, L. ; Boutillier, A.-L. ; Levi, S. ; Halle, A.DZNE* ; Lopes, L. V. ; Blum, D. (Corresponding author)

2019
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awz288

Abstract: 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.

Keyword(s): Animals (MeSH) ; Autopsy (MeSH) ; Complement C1q: metabolism (MeSH) ; Frontotemporal Lobar Degeneration: genetics (MeSH) ; Frontotemporal Lobar Degeneration: metabolism (MeSH) ; Hippocampus: metabolism (MeSH) ; Hippocampus: pathology (MeSH) ; Humans (MeSH) ; Memory Disorders: etiology (MeSH) ; Memory Disorders: psychology (MeSH) ; Mice (MeSH) ; Mice, Transgenic (MeSH) ; Mutation (MeSH) ; Neurons: metabolism (MeSH) ; Receptor, Adenosine A2A: genetics (MeSH) ; Receptor, Adenosine A2A: metabolism (MeSH) ; Spatial Learning (MeSH) ; Synapses: pathology (MeSH) ; Tauopathies: genetics (MeSH) ; Tauopathies: pathology (MeSH) ; Tauopathies: psychology (MeSH) ; tau Proteins: genetics (MeSH) ; ADORA2A protein, human ; Adora2a protein, mouse ; MAPT protein, human ; Receptor, Adenosine A2A ; tau Proteins ; Complement C1q

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Contributing Institute(s):

1. Microglia and Neuroinflammation (AG Halle)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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