Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex.
Aging
Complement C1q
Microglia
Prefrontal cortex
Pyramidal cell
cAMP
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
06 Jan 2020
06 Jan 2020
Historique:
received:
24
09
2019
accepted:
17
12
2019
entrez:
8
1
2020
pubmed:
8
1
2020
medline:
11
11
2020
Statut:
epublish
Résumé
Cognitive impairment in schizophrenia, aging, and Alzheimer's disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q. Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC. C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM. These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.
Sections du résumé
BACKGROUND
BACKGROUND
Cognitive impairment in schizophrenia, aging, and Alzheimer's disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q.
METHODS
METHODS
Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC.
RESULTS
RESULTS
C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM.
CONCLUSIONS
CONCLUSIONS
These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.
Identifiants
pubmed: 31906973
doi: 10.1186/s12974-019-1683-1
pii: 10.1186/s12974-019-1683-1
pmc: PMC6945481
doi:
Substances chimiques
Complement C1q
80295-33-6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8Subventions
Organisme : Alzheimer's Association
ID : AARF-17-533294
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIA NIH HHS
ID : AG047270
Pays : United States
Organisme : Foundation for the National Institutes of Health
ID : NS41228
Organisme : NIA NIH HHS
ID : F31 AG063425
Pays : United States
Organisme : NIDA NIH HHS
ID : R37 DA023999
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066508
Pays : United States
Organisme : NIA NIH HHS
ID : AG062306
Pays : United States
Organisme : NIDA NIH HHS
ID : DA023999
Pays : United States
Organisme : NIA NIH HHS
ID : DP1AG047744-01
Pays : United States
Références
Nat Rev Neurosci. 2008 Nov;9(11):807-11
pubmed: 18827829
Ann Neurol. 2018 Mar;83(3):544-552
pubmed: 29406582
Biochemistry. 2005 Nov 1;44(43):14097-109
pubmed: 16245926
Nat Neurosci. 2015 Oct;18(10):1376-85
pubmed: 26404712
Nat Neurosci. 2013 Dec;16(12):1896-905
pubmed: 24162652
Mol Immunol. 2011 Aug;48(14):1592-603
pubmed: 21546088
Nat Rev Neurosci. 2012 Mar 07;13(4):240-50
pubmed: 22395804
Nature. 2016 Feb 11;530(7589):177-83
pubmed: 26814963
Neuroscience. 2009 Sep 15;162(4):1192-201
pubmed: 19463906
Cell. 2016 May 5;165(4):921-35
pubmed: 27114033
Mol Neurobiol. 2019 Aug;56(8):5568-5585
pubmed: 30652266
J Neuroinflammation. 2017 Mar 6;14(1):48
pubmed: 28264694
Neurosci Biobehav Rev. 2003 Oct;27(6):555-79
pubmed: 14599436
Science. 2013 Jun 21;340(6139):1475-8
pubmed: 23722427
J Neurosci. 2014 Sep 3;34(36):11929-47
pubmed: 25186741
Am J Anat. 1970 Apr;127(4):321-55
pubmed: 4985058
Nat Neurosci. 2016 Mar;19(3):504-16
pubmed: 26780511
Neuroscience. 2008 Apr 9;152(4):970-81
pubmed: 18329176
Neuron. 2018 Dec 19;100(6):1322-1336.e7
pubmed: 30392797
Cell. 2018 May 17;173(5):1073-1081
pubmed: 29775591
Neurobiol Aging. 2017 Mar;51:9-18
pubmed: 28027494
Nature. 2017 Jan 26;541(7638):481-487
pubmed: 28099414
Immunity. 2019 Jan 15;50(1):253-271.e6
pubmed: 30471926
Trends Neurosci. 2013 Apr;36(4):209-17
pubmed: 23260014
Brain Res Rev. 2010 Mar;62(2):212-32
pubmed: 20005254
Neuron. 2013 Jan 9;77(1):10-8
pubmed: 23312512
Science. 2016 May 6;352(6286):712-716
pubmed: 27033548
J Clin Invest. 2004 Sep;114(5):679-88
pubmed: 15343386
Am J Pathol. 1999 Mar;154(3):927-36
pubmed: 10079271
Annu Rev Neurosci. 2012;35:369-89
pubmed: 22715882
Arch Gen Psychiatry. 2000 Jan;57(1):65-73
pubmed: 10632234
Cereb Cortex. 2013 Jul;23(7):1643-54
pubmed: 22693343
J Neuroinflammation. 2009 Nov 17;6:35
pubmed: 19917141
Mol Immunol. 2008 Jun;45(11):3244-52
pubmed: 18400300
Nat Neurosci. 2019 Mar;22(3):374-385
pubmed: 30718903
Neuron. 2018 Dec 19;100(6):1337-1353.e5
pubmed: 30415998
Cell. 2007 Dec 14;131(6):1164-78
pubmed: 18083105
Mediators Inflamm. 2018 Nov 11;2018:2530414
pubmed: 30533998
Sci Rep. 2018 Mar 20;8(1):4908
pubmed: 29559654
Cell. 2010 May 28;141(5):859-71
pubmed: 20510932
J Neurosci. 2004 Jun 9;24(23):5292-300
pubmed: 15190100
Ann Neurol. 1990 May;27(5):457-64
pubmed: 2360787
Nat Rev Immunol. 2018 Apr;18(4):225-242
pubmed: 29151590
Neuron. 2012 Oct 4;76(1):223-39
pubmed: 23040817
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1896-E1905
pubmed: 29437957
Immunity. 2018 Feb 20;48(2):380-395.e6
pubmed: 29426702
Cold Spring Harb Perspect Biol. 2015 Feb 06;7(9):a020370
pubmed: 25663667
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):486-91
pubmed: 24297907
Nature. 2011 Jul 27;476(7359):210-3
pubmed: 21796118
Cell. 2004 Dec 17;119(6):873-87
pubmed: 15607982
Nat Rev Immunol. 2011 Jun;11(6):389-402
pubmed: 21597473
Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):5036-41
pubmed: 24707050
Proc Natl Acad Sci U S A. 2016 Mar 22;113(12):E1738-46
pubmed: 26884166
Cereb Cortex. 2003 Sep;13(9):950-61
pubmed: 12902394
J Neurosci. 2010 Jun 2;30(22):7507-15
pubmed: 20519525
Neurosci Lett. 2019 Aug 10;707:134317
pubmed: 31175934
J Neurosci. 2013 Aug 14;33(33):13460-74
pubmed: 23946404
Proc Natl Acad Sci U S A. 2015 Sep 8;112(36):11389-94
pubmed: 26217001
J Neurosci. 2011 May 25;31(21):7831-9
pubmed: 21613496
Brain Res. 1997 Sep 26;769(2):391-5
pubmed: 9374212
Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6303-6308
pubmed: 29844190
Exp Neurol. 1996 Mar;138(1):22-32
pubmed: 8593893
Nat Neurosci. 2013 Dec;16(12):1773-82
pubmed: 24162655
Alzheimers Dement. 2018 May;14(5):680-691
pubmed: 29241829
Neuron. 2002 Aug 1;35(3):419-32
pubmed: 12165466
Neuron. 2012 May 24;74(4):691-705
pubmed: 22632727
Free Radic Biol Med. 2016 Nov;100:108-122
pubmed: 27154981
Nat Neurosci. 2017 Aug;20(8):1162-1171
pubmed: 28671693
Nat Neurosci. 2015 Nov;18(11):1539-1545
pubmed: 26505565