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C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer's disease mouse model.

التفاصيل البيبلوغرافية
العنوان: C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer's disease mouse model.
المؤلفون: Schartz ND; Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA., Liang HY; Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA, USA., Carvalho K; Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA, USA., Chu SH; Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA., Mendoza-Arvilla A; Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA., Petrisko TJ; Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA., Gomez-Arboledas A; Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA., Mortazavi A; Department of Developmental & Cell Biology, University of California, Irvine, Irvine, CA, USA., Tenner AJ; Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA, USA. atenner@uci.edu.; Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA. atenner@uci.edu.; Department of Pathology and Laboratory Medicine, University of California, Irvine, School of Medicine, Irvine, CA, USA. atenner@uci.edu.
المصدر: Nature communications [Nat Commun] 2024 Aug 15; Vol. 15 (1), pp. 7028. Date of Electronic Publication: 2024 Aug 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Receptor, Anaphylatoxin C5a*/antagonists & inhibitors , Receptor, Anaphylatoxin C5a*/metabolism , Receptor, Anaphylatoxin C5a*/genetics , Alzheimer Disease*/metabolism , Alzheimer Disease*/drug therapy , Alzheimer Disease*/pathology , Alzheimer Disease*/genetics , Disease Models, Animal* , Signal Transduction*/drug effects , Microglia*/drug effects , Microglia*/metabolism , Hippocampus*/metabolism , Hippocampus*/pathology , Hippocampus*/drug effects, Animals ; Mice ; Female ; Male ; Neuroglia/drug effects ; Neuroglia/metabolism ; Astrocytes/drug effects ; Astrocytes/metabolism ; Mice, Transgenic ; Humans ; Mice, Inbred C57BL
مستخلص: Alzheimer's disease (AD) is the leading cause of dementia in older adults, and the need for effective, sustainable therapeutic targets is imperative. The complement pathway has been proposed as a therapeutic target. C5aR1 inhibition reduces plaque load, gliosis, and memory deficits in animal models, however, the cellular bases underlying this neuroprotection were unclear. Here, we show that the C5aR1 antagonist PMX205 improves outcomes in the Arctic48 mouse model of AD. A combination of single cell and single nucleus RNA-seq analysis of hippocampi derived from males and females identified neurotoxic disease-associated microglia clusters in Arctic mice that are C5aR1-dependent, while microglial genes associated with synapse organization and transmission and learning were overrepresented in PMX205-treated mice. PMX205 also reduced neurotoxic astrocyte gene expression, but clusters associated with protective responses to injury were unchanged. C5aR1 inhibition promoted mRNA-predicted signaling pathways between brain cell types associated with cell growth and repair, while suppressing inflammatory pathways. Finally, although hippocampal plaque load was unaffected, PMX205 prevented deficits in short-term memory in female Arctic mice. In conclusion, C5aR1 inhibition prevents cognitive loss, limits detrimental glial polarization while permitting neuroprotective responses, as well as leaving most protective functions of complement intact, making C5aR1 antagonism an attractive therapeutic strategy for AD.
(© 2024. The Author(s).)
التعليقات: Update of: bioRxiv. 2023 Aug 22:2023.08.22.554306. doi: 10.1101/2023.08.22.554306. (PMID: 37662399)
References: Cell. 2017 Jun 15;169(7):1276-1290.e17. (PMID: 28602351)
Cell Rep. 2019 Aug 20;28(8):2111-2123.e6. (PMID: 31433986)
Arthritis Rheumatol. 2019 Sep;71(9):1413-1425. (PMID: 31102496)
Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6303-6308. (PMID: 29844190)
Semin Immunopathol. 2018 Jan;40(1):113-124. (PMID: 29134267)
Genome Biol. 2021 Oct 7;22(1):286. (PMID: 34620214)
Trends Immunol. 2010 Apr;31(4):154-63. (PMID: 20153254)
Nat Aging. 2024 Jan;4(1):33-47. (PMID: 38195725)
Alzheimers Dement. 2018 Apr;14(4):535-562. (PMID: 29653606)
Nat Med. 1997 Jan;3(1):77-9. (PMID: 8986745)
J Neuroinflammation. 2013 Sep 26;10:119. (PMID: 24067070)
Neurobiol Aging. 2015 Feb;36(2):821-31. (PMID: 25457554)
J Neuroinflammation. 2017 Mar 6;14(1):48. (PMID: 28264694)
Neurosci Lett. 2014 Apr 17;565:30-8. (PMID: 24406153)
J Biol Chem. 2013 Jan 4;288(1):654-65. (PMID: 23150673)
Br J Pharmacol. 2023 Aug;180(16):2140-2155. (PMID: 36929333)
Neurosci Lett. 2001 Jun 15;305(3):165-8. (PMID: 11403931)
Alzheimers Dement. 2024 Mar;20(3):2173-2190. (PMID: 38278523)
eNeuro. 2022 Jan 18;9(1):. (PMID: 34880111)
EMBO J. 2020 Aug 17;39(16):e105380. (PMID: 32657463)
Nature. 2017 Jan 26;541(7638):481-487. (PMID: 28099414)
Neural Plast. 2017;2017:2740768. (PMID: 28197342)
J Immunol. 2020 Jan 15;204(2):306-315. (PMID: 31907273)
Genes Dev. 2021 Feb 1;35(3-4):180-198. (PMID: 33526585)
Alzheimers Dement. 2022 Feb;18(2):360-376. (PMID: 34223696)
Br J Pharmacol. 2017 Apr;174(8):689-699. (PMID: 28128456)
Cell. 2023 Sep 28;186(20):4386-4403.e29. (PMID: 37774678)
Science. 2021 Sep 10;373(6560):eabj2685. (PMID: 34516796)
Front Immunol. 2020 Apr 23;11:724. (PMID: 32391019)
Cell. 2023 Jun 22;186(13):2802-2822.e22. (PMID: 37220746)
Mol Neurobiol. 2021 Aug;58(8):3884-3902. (PMID: 33860438)
Mol Neurodegener. 2022 Dec 23;17(1):84. (PMID: 36564824)
Biochem Pharmacol. 2020 Oct;180:114156. (PMID: 32682759)
Cell. 2021 Jun 24;184(13):3573-3587.e29. (PMID: 34062119)
Front Immunol. 2021 Feb 25;12:629986. (PMID: 33717157)
Biochem Biophys Res Commun. 2000 Jun 24;273(1):364-9. (PMID: 10873612)
Nat Neurosci. 2019 Oct;22(10):1696-1708. (PMID: 31551601)
J Immunol. 2009 Jul 15;183(2):1375-83. (PMID: 19561098)
Mol Immunol. 2017 Sep;89:36-43. (PMID: 28576324)
Matrix Biol. 2022 Jun;110:1-15. (PMID: 35430380)
Nat Neurosci. 2014 Jan;17(1):131-43. (PMID: 24316888)
Nat Commun. 2021 Feb 17;12(1):1088. (PMID: 33597522)
Mol Immunol. 2018 Oct;102:73-83. (PMID: 30217334)
Mol Psychiatry. 2020 Jan;25(1):114-130. (PMID: 31439935)
Sci Adv. 2021 Jan 6;7(2):. (PMID: 33523961)
Dis Markers. 2022 Apr 25;2022:4535652. (PMID: 35510037)
FASEB J. 2012 Sep;26(9):3680-90. (PMID: 22651932)
Acta Neuropathol Commun. 2022 Jul 6;10(1):99. (PMID: 35794654)
J Neurosci. 2015 Jul 15;35(28):10217-23. (PMID: 26180198)
Proc Natl Acad Sci U S A. 2024 Jan 30;121(5):e2314627121. (PMID: 38252818)
Biochim Biophys Acta. 2016 Oct;1862(10):1847-60. (PMID: 27425031)
Mol Neurodegener. 2017 Sep 18;12(1):66. (PMID: 28923083)
Cell. 2007 Dec 14;131(6):1164-78. (PMID: 18083105)
Mol Immunol. 2015 Dec;68(2 Pt A):253-60. (PMID: 26383831)
Annu Rev Immunol. 2023 Apr 26;41:431-452. (PMID: 36750318)
J Neuroinflammation. 2022 Jul 11;19(1):178. (PMID: 35820938)
J Neurochem. 2010 Apr;113(2):389-401. (PMID: 20132482)
Cell Syst. 2019 Apr 24;8(4):281-291.e9. (PMID: 30954476)
ACS Omega. 2020 Jan 30;5(5):2345-2354. (PMID: 32064396)
Alzheimers Dement. 2022 Apr;18(4):700-789. (PMID: 35289055)
Nat Med. 2004 Nov;10(11):1190-2. (PMID: 15502844)
Semin Immunol. 2019 Oct;45:101340. (PMID: 31708347)
Expert Opin Ther Targets. 2023 Feb;27(2):97-109. (PMID: 36786123)
Neurobiol Learn Mem. 2000 Jan;73(1):31-48. (PMID: 10686122)
Cell. 2016 Feb 11;164(4):603-15. (PMID: 26871627)
Nat Neurosci. 2023 Jul;26(7):1185-1195. (PMID: 37277487)
J Neurotrauma. 2017 Jun 15;34(12):2075-2085. (PMID: 28173736)
Neuron. 2022 Jun 1;110(11):1788-1805.e10. (PMID: 35381189)
J Neuroinflammation. 2020 Nov 25;17(1):354. (PMID: 33239010)
J Neuroinflammation. 2015 Aug 16;12:150. (PMID: 26275910)
Brain Behav Immun. 2016 Jul;55:179-190. (PMID: 26541819)
J Neuroinflammation. 2014 Apr 16;11:76. (PMID: 24735639)
Adv Immunol. 2021;152:157-222. (PMID: 34844709)
Mol Genet Genomic Med. 2022 Jun;10(6):e1942. (PMID: 35488718)
Brain Behav Immun. 2017 Mar;61:209-216. (PMID: 27890662)
Acta Neuropathol Commun. 2018 May 3;6(1):36. (PMID: 29724241)
Nat Commun. 2019 Apr 3;10(1):1523. (PMID: 30944313)
Prog Neurobiol. 2022 Jul;214:102282. (PMID: 35533811)
Mol Neurodegener. 2019 Aug 2;14(1):32. (PMID: 31375134)
Science. 2020 Feb 7;367(6478):688-694. (PMID: 32029629)
Adv Exp Med Biol. 2006;586:153-76. (PMID: 16893071)
Neurobiol Aging. 1997 Jul-Aug;18(4):415-21. (PMID: 9330973)
Acta Neuropathol Commun. 2022 Aug 17;10(1):116. (PMID: 35978440)
Nat Neurosci. 2022 Mar;25(3):306-316. (PMID: 35260865)
J Immunol. 2009 Nov 15;183(10):6175-85. (PMID: 19864605)
Br J Pharmacol. 2021 Jul;178(14):2754-2770. (PMID: 32562277)
J Innate Immun. 2023;15(1):468-484. (PMID: 36882040)
معلومات مُعتمدة: 2021-A-020-FEL Larry L. Hillblom Foundation (Larry L. Hillblom Foundation, Inc.); T32 AG00096 U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER); AARFD-20-677771 United States ALZ Alzheimer's Association; T32 AG000096 United States AG NIA NIH HHS; P30 CA062203 United States CA NCI NIH HHS; R01 AG060148 United States AG NIA NIH HHS; P50 GM076516 United States GM NIGMS NIH HHS; AG060148 U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)
المشرفين على المادة: 0 (Receptor, Anaphylatoxin C5a)
0 (C5ar1 protein, mouse)
تواريخ الأحداث: Date Created: 20240815 Date Completed: 20240815 Latest Revision: 20240820
رمز التحديث: 20240820
مُعرف محوري في PubMed: PMC11327341
DOI: 10.1038/s41467-024-51163-6
PMID: 39147742
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-51163-6