Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor.
Animals
Autopsy
Complement C1q
/ metabolism
Frontotemporal Lobar Degeneration
/ genetics
Hippocampus
/ metabolism
Humans
Memory Disorders
/ etiology
Mice
Mice, Transgenic
Mutation
Neurons
/ metabolism
Receptor, Adenosine A2A
/ genetics
Spatial Learning
Synapses
/ pathology
Tauopathies
/ genetics
tau Proteins
/ genetics
A2A receptor
C1q
adenosine
microglia
tau
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
01 11 2019
01 11 2019
Historique:
received:
19
03
2019
revised:
24
07
2019
accepted:
26
07
2019
pubmed:
11
10
2019
medline:
27
5
2020
entrez:
11
10
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31599329
pii: 5584878
doi: 10.1093/brain/awz288
pmc: PMC6821333
doi:
Substances chimiques
ADORA2A protein, human
0
Adora2a protein, mouse
0
MAPT protein, human
0
Receptor, Adenosine A2A
0
tau Proteins
0
Complement C1q
80295-33-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3636-3654Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.
Références
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Nat Commun. 2016 Jun 17;7:11915
pubmed: 27312972
J Exp Med. 2013 Jan 14;210(1):157-72
pubmed: 23296467
Genome Biol. 2009;10(11):R134
pubmed: 19930550
EMBO Mol Med. 2018 Nov;10(11):
pubmed: 30275019
Nucleic Acids Res. 1987 Oct 26;15(20):8125-48
pubmed: 3313277
Nature. 2016 Jun 22;534(7608):538-43
pubmed: 27337340
J Neuroinflammation. 2017 Mar 6;14(1):48
pubmed: 28264694
Brain. 2018 Feb 1;141(2):521-534
pubmed: 29253099
Cell. 2017 Jun 15;169(7):1276-1290.e17
pubmed: 28602351
Mol Psychiatry. 2016 Jan;21(1):97-107
pubmed: 25450226
J Neurosci. 2014 Sep 3;34(36):11929-47
pubmed: 25186741
Aging Cell. 2013 Feb;12(1):11-23
pubmed: 23082852
Brain. 2017 Jan;140(1):184-200
pubmed: 27818384
J Neurosci. 2009 Nov 25;29(47):14741-51
pubmed: 19940169
Semin Cell Dev Biol. 2018 Dec 4;:null
pubmed: 30529149
Neuron. 2018 Dec 19;100(6):1322-1336.e7
pubmed: 30392797
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
J Neurochem. 1987 Dec;49(6):1927-40
pubmed: 2824699
Glia. 2019 Dec;67(12):2329-2342
pubmed: 31328322
J Neurophysiol. 2003 Aug;90(2):1295-303
pubmed: 12904509
J Neurosci. 1988 Mar;8(3):1039-51
pubmed: 3346714
Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):7833-8
pubmed: 26056314
Sci Rep. 2016 Aug 11;6:31493
pubmed: 27510168
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nat Neurosci. 2015 Mar;18(3):423-34
pubmed: 25622143
Lancet Neurol. 2003 Jun;2(6):366-74
pubmed: 12849153
Mol Psychiatry. 2018 Jun 27;:null
pubmed: 29950682
Mov Disord. 2016 Dec;31(12):1883-1890
pubmed: 27709663
Hum Mol Genet. 2015 Nov 1;24(21):5965-76
pubmed: 26358780
Nature. 2013 Sep 5;501(7465):45-51
pubmed: 24005412
Science. 2016 May 6;352(6286):712-716
pubmed: 27033548
Expert Rev Proteomics. 2008 Apr;5(2):207-24
pubmed: 18466052
Neurobiol Aging. 2009 Nov;30(11):1877-84
pubmed: 18304697
Diabetes. 2013 May;62(5):1681-8
pubmed: 23250356
Front Immunol. 2016 Nov 29;7:544
pubmed: 27965671
Biotechnol J. 2007 Aug;2(8):967-77
pubmed: 17571276
J Neurosci. 2012 Aug 1;32(31):10574-86
pubmed: 22855807
J Neurosci. 1990 Jun;10(6):1788-98
pubmed: 2162385
Neuron. 2014 May 21;82(4):756-71
pubmed: 24853936
Front Mol Neurosci. 2018 Jul 12;11:235
pubmed: 30050407
Acta Neuropathol Commun. 2015 May 23;3:31
pubmed: 26001565
Epilepsy Behav. 2019 Jul;96:192-199
pubmed: 31150999
Biol Psychiatry. 2018 Jan 1;83(1):38-49
pubmed: 28697890
Acta Neuropathol. 2015 May;129(5):749-56
pubmed: 25628035
Neurobiol Dis. 2018 Sep;117:72-81
pubmed: 29859867
Aging Cell. 2014 Aug;13(4):584-95
pubmed: 24641683
Neurobiol Dis. 2004 Feb;15(1):40-6
pubmed: 14751769
J Alzheimers Dis. 2013;37(4):777-88
pubmed: 23948912
Genome Biol. 2010;11(10):R106
pubmed: 20979621
J Neurochem. 2016 Dec;139(6):1019-1055
pubmed: 27365148
J Neurosci. 2013 Jul 10;33(28):11390-9
pubmed: 23843511
Bioinformatics. 2009 May 1;25(9):1105-11
pubmed: 19289445
Neurobiol Dis. 2004 Dec;17(3):359-66
pubmed: 15571972
Curr Alzheimer Res. 2009 Apr;6(2):152-7
pubmed: 19355850
Neurobiol Dis. 2019 Aug 5;132:104570
pubmed: 31394204
Mol Neurobiol. 2017 Mar;54(2):1552-1563
pubmed: 26860412
Am J Pathol. 2006 Aug;169(2):599-616
pubmed: 16877359
Neurobiol Dis. 2018 Feb;110:29-36
pubmed: 29100987
Eur J Neurosci. 2011 Jul;34(1):12-21
pubmed: 21615561
Acta Neuropathol. 2017 May;133(5):705-715
pubmed: 28160067
Brain Pathol. 2008 Apr;18(2):211-9
pubmed: 18241242
eNeuro. 2018 Dec 26;5(6):
pubmed: 30627646
Nat Commun. 2016 Apr 21;7:11295
pubmed: 27097852
Nature. 1998 Jun 18;393(6686):702-5
pubmed: 9641683
Neurobiol Aging. 1999 Nov-Dec;20(6):573-9
pubmed: 10674422
Cell Rep. 2017 Oct 10;21(2):366-380
pubmed: 29020624
Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):E3755-63
pubmed: 27274066
Mol Psychiatry. 2019 Sep;24(9):1383-1397
pubmed: 30283031
Neurobiol Learn Mem. 2011 Mar;95(3):296-304
pubmed: 21167950
Neurobiol Aging. 2018 Oct;70:128-139
pubmed: 30007162
Brain Pathol. 2006 Oct;16(4):249-55
pubmed: 17107593
Nucleic Acids Res. 2017 Jan 4;45(D1):D362-D368
pubmed: 27924014
Nat Rev Neurosci. 2018 Oct;19(10):622-635
pubmed: 30206328
J Neurosci. 2013 Aug 14;33(33):13460-74
pubmed: 23946404
Nat Neurosci. 2016 Jan;19(1):94-101
pubmed: 26642091
Glia. 2018 Jul;66(7):1464-1480
pubmed: 29493017
J Neurochem. 2016 Aug;138 Suppl 1:54-70
pubmed: 27306735
Curr Opin Neurol. 2017 Dec;30(6):589-598
pubmed: 28914736
Mol Psychiatry. 2013 Mar;18(3):320-31
pubmed: 22371048
Curr Alzheimer Res. 2011 Sep;8(6):633-8
pubmed: 21605043
J Neurochem. 1999 Oct;73(4):1733-8
pubmed: 10501222
Mol Neurobiol. 2018 Dec;55(12):8936-8952
pubmed: 29616397
Neuron. 2012 May 24;74(4):691-705
pubmed: 22632727
Neurobiol Aging. 1997 May-Jun;18(3):267-73
pubmed: 9263190
Mol Psychiatry. 2015 Nov;20(11):1339-49
pubmed: 25687775
J Alzheimers Dis. 2012;31(3):555-67
pubmed: 22647260