C5aR1 signaling promotes region and age dependent synaptic pruning in models of Alzheimer's Disease.
Alzheimer’s disease
C1q
C5aR1
microglia
synaptic pruning
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
02 Oct 2023
02 Oct 2023
Historique:
pubmed:
24
10
2023
medline:
24
10
2023
entrez:
24
10
2023
Statut:
epublish
Résumé
Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD. A combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD. Genetic ablation or pharmacological inhibition of C5aR1 rescues the excessive pre-synaptic pruning and synaptic loss in an age and region dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP). Reduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.
Identifiants
pubmed: 37873302
doi: 10.1101/2023.09.29.560234
pmc: PMC10592845
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NIA NIH HHS
ID : U54 AG054349
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG061746
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM076516
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG076835
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA062203
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG060148
Pays : United States
Déclaration de conflit d'intérêts
Disclosures: Authors declare no conflict of interest.
Références
Cell. 2016 May 5;165(4):921-35
pubmed: 27114033
J Neuroinflammation. 2009 Nov 16;6:34
pubmed: 19917081
Trends Neurosci. 2020 Dec;43(12):965-979
pubmed: 33127097
Alzheimers Dement. 2022 Dec;18(12):2527-2536
pubmed: 35174954
Nat Commun. 2018 Mar 26;9(1):1228
pubmed: 29581545
Science. 1996 Oct 4;274(5284):99-102
pubmed: 8810256
Nat Rev Neurosci. 2014 Apr;15(4):209-16
pubmed: 24646669
Ann Neurol. 1991 Oct;30(4):572-80
pubmed: 1789684
Genes (Basel). 2021 Mar 20;12(3):
pubmed: 33804666
Neurobiol Aging. 2000 May-Jun;21(3):383-421
pubmed: 10858586
J Neuroinflammation. 2017 Mar 6;14(1):48
pubmed: 28264694
JMIR Res Protoc. 2020 Apr 7;9(4):e16664
pubmed: 32088663
Neuroreport. 1997 Nov 10;8(16):3457-62
pubmed: 9427307
Sci Transl Med. 2017 May 31;9(392):
pubmed: 28566429
J Biol Chem. 2013 Jan 4;288(1):654-65
pubmed: 23150673
Science. 2002 Oct 25;298(5594):789-91
pubmed: 12399581
Neuron. 2018 Oct 10;100(1):120-134.e6
pubmed: 30308165
Neuron. 2018 Dec 19;100(6):1322-1336.e7
pubmed: 30392797
Mol Immunol. 2011 Aug;48(14):1631-42
pubmed: 21549429
Neurosci Lett. 2001 Jun 15;305(3):165-8
pubmed: 11403931
Fac Rev. 2021 Feb 24;10:19
pubmed: 33718936
N Engl J Med. 2021 Feb 18;384(7):599-609
pubmed: 33596356
Immunity. 2023 Aug 8;56(8):1794-1808.e8
pubmed: 37442133
Cell Rep. 2019 Aug 20;28(8):2111-2123.e6
pubmed: 31433986
Science. 2016 May 6;352(6286):712-716
pubmed: 27033548
Annu Rev Neurosci. 2012;35:369-89
pubmed: 22715882
Prog Neurobiol. 2020 Nov;194:101801
pubmed: 32428558
N Engl J Med. 2010 Jan 28;362(4):329-44
pubmed: 20107219
J Immunol. 2009 Jul 15;183(2):1375-83
pubmed: 19561098
Nature. 2021 Feb;590(7847):612-617
pubmed: 33361813
Front Immunol. 2021 Feb 08;11:599771
pubmed: 33628204
Mol Cell Proteomics. 2020 Jan;19(1):128-141
pubmed: 31699905
Nat Aging. 2022 Sep;2(9):837-850
pubmed: 37118504
J Neuroinflammation. 2012 Jul 23;9:179
pubmed: 22824372
Curr Opin Neurobiol. 2017 Aug;45:9-15
pubmed: 28219683
J Neurosci. 2001 Sep 15;21(18):7340-8
pubmed: 11549744
Alzheimers Dement. 2016 Jun;12(6):633-44
pubmed: 26776762
Mol Neurodegener. 2017 Sep 18;12(1):66
pubmed: 28923083
Cell. 2007 Dec 14;131(6):1164-78
pubmed: 18083105
Annu Rev Immunol. 2023 Apr 26;41:431-452
pubmed: 36750318
EMBO J. 2023 Oct 4;42(19):e113246
pubmed: 37575021
Nature. 2016 Feb 11;530(7589):177-83
pubmed: 26814963
Immunity. 2020 Jan 14;52(1):167-182.e7
pubmed: 31883839
J Neuroinflammation. 2022 Jul 11;19(1):178
pubmed: 35820938
J Neurochem. 2010 Apr;113(2):389-401
pubmed: 20132482
Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10016-20
pubmed: 1438191
Front Cell Neurosci. 2022 Jun 16;16:899251
pubmed: 35783099
Immunotargets Ther. 2021 Sep 24;10:373-386
pubmed: 34595138
J Neuroinflammation. 2020 Nov 25;17(1):354
pubmed: 33239010
J Neuroinflammation. 2015 Aug 16;12:150
pubmed: 26275910
Sci Transl Med. 2023 Mar 29;15(689):eadf0141
pubmed: 36989373
J Neurochem. 2008 Sep;106(5):2080-92
pubmed: 18624920
Acta Neuropathol. 1996;91(1):53-60
pubmed: 8773146
Adv Immunol. 2021;152:157-222
pubmed: 34844709
J Neurosci. 2013 Aug 14;33(33):13460-74
pubmed: 23946404
Nature. 2013 Dec 19;504(7480):394-400
pubmed: 24270812
Rheumatology (Oxford). 2007 Dec;46(12):1773-8
pubmed: 17965442
Semin Cell Dev Biol. 2023 Apr;139:13-23
pubmed: 35690535
Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6303-6308
pubmed: 29844190
Ann Neurol. 2022 Dec;92(6):1001-1015
pubmed: 36056679
Prog Neurobiol. 2022 Jul;214:102282
pubmed: 35533811
Exp Neurol. 1996 Mar;138(1):22-32
pubmed: 8593893
Acta Neuropathol Commun. 2022 Aug 17;10(1):116
pubmed: 35978440
Neuron. 2012 May 24;74(4):691-705
pubmed: 22632727
Neuromolecular Med. 2010 Jun;12(2):179-92
pubmed: 19763906
Science. 2020 Aug 28;369(6507):
pubmed: 32855309
Cold Spring Harb Perspect Med. 2012 Jan;2(1):a006346
pubmed: 22315714
J Neuroinflammation. 2011 Jan 15;8(1):4
pubmed: 21235806