C5aR1 antagonism alters microglial polarization and mitigates disease progression in a mouse model of Alzheimer's disease.
Alzheimer’s disease
C5aR1
Complement
DAM
Microglia
Neuroinflammation
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
17 08 2022
17 08 2022
Historique:
received:
09
06
2022
accepted:
29
07
2022
entrez:
17
8
2022
pubmed:
18
8
2022
medline:
20
8
2022
Statut:
epublish
Résumé
Multiple studies have recognized the involvement of the complement cascade during Alzheimer's disease pathogenesis. However, the specific role of C5a-C5aR1 signaling in the progression of this neurodegenerative disease is still not clear. Furthermore, its potential as a therapeutic target to treat AD still remains to be elucidated. Canonically, generation of the anaphylatoxin C5a as the result of complement activation and interaction with its receptor C5aR1 triggers a potent inflammatory response. Previously, genetic ablation of C5aR1 in a mouse model of Alzheimer's disease exerted a protective effect by preventing cognitive deficits. Here, using PMX205, a potent, specific C5aR1 antagonist, in the Tg2576 mouse model of Alzheimer's disease we show a striking reduction in dystrophic neurites in parallel with the reduced amyloid load, rescue of the excessive pre-synaptic loss associated with AD cognitive impairment and the polarization of microglial gene expression towards a DAM-like phenotype that are consistent with the neuroprotective effects seen. These data support the beneficial effect of a pharmacological inhibition of C5aR1 as a promising therapeutic approach to treat Alzheimer's disease. Supportive of the safety of this treatment is the recent FDA-approval of another other C5a receptor 1 antagonist, Avacopan, as a treatment for autoimmune inflammatory diseases.
Identifiants
pubmed: 35978440
doi: 10.1186/s40478-022-01416-6
pii: 10.1186/s40478-022-01416-6
pmc: PMC9386996
doi:
Substances chimiques
C5ar1 protein, mouse
0
Receptor, Anaphylatoxin C5a
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
116Subventions
Organisme : NIA NIH HHS
ID : T32 AG000096
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM076516
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA062203
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG060148
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG061746
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Genes (Basel). 2021 Dec 15;12(12):
pubmed: 34946939
Mol Neurodegener. 2018 May 21;13(1):24
pubmed: 29784049
Cell. 2016 May 5;165(4):921-35
pubmed: 27114033
Alzheimers Res Ther. 2020 Mar 2;12(1):21
pubmed: 32122400
Ann Neurol. 1991 Oct;30(4):572-80
pubmed: 1789684
Front Mol Neurosci. 2021 Jul 23;14:713031
pubmed: 34366786
Nat Med. 2014 Oct;20(10):1157-64
pubmed: 25261995
Genes (Basel). 2021 Mar 20;12(3):
pubmed: 33804666
Neurobiol Aging. 2000 May-Jun;21(3):383-421
pubmed: 10858586
Brain Res. 2014 Oct 17;1585:1-12
pubmed: 25130661
Mol Ther. 2015 Nov;23(11):1712-1721
pubmed: 26227349
Cell. 2017 Jun 15;169(7):1276-1290.e17
pubmed: 28602351
Sci Transl Med. 2017 May 31;9(392):
pubmed: 28566429
PLoS One. 2020 Dec 1;15(12):e0241315
pubmed: 33259479
Science. 2002 Oct 25;298(5594):789-91
pubmed: 12399581
Mol Immunol. 2011 Aug;48(14):1631-42
pubmed: 21549429
J Biol Chem. 2013 Jan 4;288(1):654-65
pubmed: 23150673
Am J Med Genet A. 2009 Feb 15;149A(4):613-21
pubmed: 19267410
Cell. 2018 May 17;173(5):1073-1081
pubmed: 29775591
J Pharmacol Exp Ther. 2005 Aug;314(2):811-7
pubmed: 15879003
J Neuroinflammation. 2013 Feb 08;10:25
pubmed: 23394121
J Immunol. 2020 Jan 15;204(2):306-315
pubmed: 31907273
N Engl J Med. 2021 Feb 18;384(7):599-609
pubmed: 33596356
Nat Biotechnol. 2016 May;34(5):525-7
pubmed: 27043002
Br J Pharmacol. 2017 Apr;174(8):689-699
pubmed: 28128456
Biochim Biophys Acta. 2012 Mar;1822(3):370-9
pubmed: 22108203
J Exp Med. 2016 May 2;213(5):667-75
pubmed: 27091843
Science. 1992 Apr 10;256(5054):184-5
pubmed: 1566067
J Immunol. 2012 Jun 1;188(11):5682-93
pubmed: 22523386
J Exp Med. 2018 Sep 3;215(9):2235-2245
pubmed: 30082275
Science. 2016 May 6;352(6286):712-716
pubmed: 27033548
Arch Neurol. 2009 Dec;66(12):1469-75
pubmed: 20008650
Sci Rep. 2015 Oct 29;5:15862
pubmed: 26511387
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
Mol Psychiatry. 2018 Feb;23(2):177-198
pubmed: 29230021
J Immunol. 2009 Jul 15;183(2):1375-83
pubmed: 19561098
Nat Commun. 2015 Jan 29;6:6176
pubmed: 25630253
Acta Neuropathol Commun. 2015 May 23;3:31
pubmed: 26001565
EMBO Mol Med. 2016 Sep 01;8(9):992-1004
pubmed: 27402340
Glia. 2016 Dec;64(12):2274-2290
pubmed: 27658617
J Immunol. 2019 Jun 15;202(12):3339-3348
pubmed: 31160390
Nat Commun. 2021 Feb 17;12(1):1088
pubmed: 33597522
Nat Commun. 2019 Aug 21;10(1):3758
pubmed: 31434879
J Neurosci. 2011 Jan 26;31(4):1355-65
pubmed: 21273420
Alzheimers Res Ther. 2017 Mar 4;9(1):14
pubmed: 28259169
Nat Immunol. 2021 May;22(5):586-594
pubmed: 33859405
Mol Neurodegener. 2017 Sep 18;12(1):66
pubmed: 28923083
Cell. 2007 Dec 14;131(6):1164-78
pubmed: 18083105
PLoS One. 2016 Mar 10;11(3):e0151081
pubmed: 26963387
Brain. 2016 Apr;139(Pt 4):1265-81
pubmed: 26921617
J Neuroinflammation. 2022 Jul 11;19(1):178
pubmed: 35820938
J Neurochem. 2010 Apr;113(2):389-401
pubmed: 20132482
Cell Syst. 2019 Apr 24;8(4):281-291.e9
pubmed: 30954476
ACS Omega. 2020 Jan 30;5(5):2345-2354
pubmed: 32064396
Nat Med. 2004 Nov;10(11):1190-2
pubmed: 15502844
Semin Immunol. 2019 Oct;45:101340
pubmed: 31708347
J Neurosci. 2004 Jul 21;24(29):6457-65
pubmed: 15269255
Alzheimers Dement. 2022 Feb 17;:
pubmed: 35174954
Science. 1996 Oct 4;274(5284):99-102
pubmed: 8810256
J Immunol. 2015 Apr 15;194(8):3542-8
pubmed: 25848071
J Neurotrauma. 2017 Jun 15;34(12):2075-2085
pubmed: 28173736
Immunotargets Ther. 2021 Sep 24;10:373-386
pubmed: 34595138
Nat Genet. 2019 Mar;51(3):414-430
pubmed: 30820047
J Neuroinflammation. 2020 Nov 25;17(1):354
pubmed: 33239010
J Neurochem. 2008 Sep;106(5):2080-92
pubmed: 18624920
Nat Biotechnol. 2021 Jul;39(7):813-818
pubmed: 33795888
Nat Rev Neurol. 2021 Nov;17(11):689-701
pubmed: 34522039
Neuron. 2021 Apr 21;109(8):1283-1301.e6
pubmed: 33675684
Mol Neurodegener. 2009 Oct 22;4:41
pubmed: 19849849
Brain Behav Immun Health. 2021 Oct 22;18:100370
pubmed: 34755124
J Am Soc Nephrol. 2014 Feb;25(2):225-31
pubmed: 24179165
Neurobiol Dis. 2020 Sep;143:104962
pubmed: 32535152
J Neurosci. 2015 Sep 23;35(38):13029-42
pubmed: 26400934
Exp Neurol. 1996 Mar;138(1):22-32
pubmed: 8593893
Mol Neurodegener. 2019 Aug 2;14(1):32
pubmed: 31375134
Neuron. 2012 May 24;74(4):691-705
pubmed: 22632727
Neuromolecular Med. 2010 Jun;12(2):179-92
pubmed: 19763906
J Neuroinflammation. 2018 Sep 24;15(1):276
pubmed: 30249283
Cold Spring Harb Perspect Med. 2012 Jan;2(1):a006346
pubmed: 22315714
Hum Mol Genet. 2001 Apr 15;10(9):927-40
pubmed: 11309366