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Cited by 95Alzheimer's disease research and treatmentsComplement system in diseasesNeuroinflammation and Neurodegeneration Mechanisms

Terminal complement pathway activation drives synaptic loss in Alzheimer’s disease models

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Carpanini, Sarah M., Torvell, Megan, Bevan, Ryan J., Byrne, Robert A. J., Daskoulidou, Nikoleta, Saito, Takashi, Saido, Takaomi C., Taylor, Philip R. +3 more·2022·Acta Neuropathologica Communications
DOI 10.1186/s40478-022-01404-wPMC PMC9258209
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Abstract

Complement is involved in developmental synaptic pruning and pathological synapse loss in Alzheimer’s disease. It is posited that C1 binding initiates complement activation on synapses; C3 fragments then tag them for microglial phagocytosis. However, the precise mechanisms of complement-mediated synaptic loss remain unclear, and the role of the lytic membrane attack complex (MAC) is unexplored. We here address several knowledge gaps: (i) is complement activated through to MAC at the synapse? (ii) does MAC contribute to synaptic loss? (iii) can MAC inhibition prevent synaptic loss? Novel methods were developed and optimised to quantify C1q, C3 fragments and MAC in total and regional brain homogenates and synaptoneurosomes from WT and App NL−G−F Alzheimer’s disease model mouse brains at 3, 6, 9 and 12 months of age. The impact on synapse loss of systemic treatment with a MAC blocking antibody and gene knockout of a MAC component was assessed in Alzheimer’s disease model mice. A significant increase in C1q, C3 fragments and MAC was observed in App NL−G−F mice compared to controls, increasing with age and severity. Administration of anti-C7 antibody to App NL−G−F mice modulated synapse loss, reflected by the density of dendritic spines in the vicinity of plaques. Constitutive knockout of C6 significantly reduced synapse loss in 3xTg-AD mice. We demonstrate that complement dysregulation occurs in Alzheimer’s disease mice involving the activation (C1q; C3b/iC3b) and terminal (MAC) pathways in brain areas associated with pathology. Inhibition or ablation of MAC formation reduced synapse loss in two Alzheimer’s disease mouse models, demonstrating that MAC formation is a driver of synapse loss. We suggest that MAC directly damages synapses, analogous to neuromuscular junction destruction in myasthenia gravis.

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  1. [1]DeKosky ST Scheff SW Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity Ann Neurol 1990 27 457 464 10.1002/ana.410270502 2360787 · DOI · Paper page
  2. [2]Rao JS Kellom M Kim HW Rapoport SI Reese EA Neuroinflammation and synaptic loss Neurochem Res 2012 37 903 910 10.1007/s11064-012-0708-2 22311128 PMC3478877 · DOI
  3. [3]Markiewski MM Lambris JD The role of complement in inflammatory diseases from behind the scenes into the spotlight Am J Pathol 2007 171 715 727 10.2353/ajpath.2007.070166 17640961 PMC1959484 · DOI
  4. [4]Morgan BP Harris CL Complement, a target for therapy in inflammatory and degenerative diseases Nat Rev Drug Discov 2015 14 857 877 10.1038/nrd4657 26493766 PMC7098197 · DOI
  5. [6]Lambert JC Heath S Even G Campion D Sleegers K Hiltunen M Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease Nat Genet 2009 41 1094 1099 10.1038/ng.439 19734903 · DOI · Paper page
  6. [7]Bellenguez C, Küçükali F, Jansen I, Andrade V, Moreno-Grau S, Amin N et al (2020) New insights on the genetic etiology of Alzheimer’s and related dementia. medRxiv: 2020.2010.2001.20200659 Doi 10.1101/2020.10.01.20200659 · DOI
  7. [8]Hakobyan S Harding K Aiyaz M Hye A Dobson R Baird A Complement biomarkers as predictors of disease progression in Alzheimer's disease J Alzheimers Dis 2016 54 707 716 10.3233/JAD-160420 27567854 · DOI
  8. [9]Hu WT Watts KD Tailor P Nguyen TP Howell JC Lee RC CSF complement 3 and factor H are staging biomarkers in Alzheimer's disease Acta Neuropathol Commun 2016 4 14 10.1186/s40478-016-0277-8 26887322 PMC4758165 · DOI
  9. [10]Morgan AR Touchard S O'Hagan C Sims R Majounie E Escott-Price V The correlation between inflammatory biomarkers and polygenic risk score in Alzheimer's disease J Alzheimers Dis 2017 56 25 36 10.3233/JAD-160889 27911318 · DOI
  10. [11]Rasmussen KL Nordestgaard BG Frikke-Schmidt R Nielsen SF An updated Alzheimer hypothesis: complement C3 and risk of Alzheimer's disease-a cohort study of 95,442 individuals Alzheimers Dement 2018 14 1589 1601 10.1016/j.jalz.2018.07.223 30243924 · DOI
  11. [12]Ishii T Haga S Immuno-electron-microscopic localization of complements in amyloid fibrils of senile plaques Acta Neuropathol 1984 63 296 300 10.1007/BF00687336 6382906 · DOI
  12. [13]Rogers J Cooper NR Webster S Schultz J McGeer PL Styren SD Complement activation by beta-amyloid in Alzheimer disease Proc Natl Acad Sci USA 1992 89 10016 10020 10.1073/pnas.89.21.10016 1438191 PMC50268 · DOI · Paper page
  13. [14]Veerhuis R van der Valk P Janssen I Zhan SS Van Nostrand WE Eikelenboom P Complement activation in amyloid plaques in Alzheimer's disease brains does not proceed further than C3 Virchows Arch 1995 426 603 610 10.1007/BF00192116 7655742 · DOI
  14. [15]Webster S Lue LF Brachova L Tenner AJ McGeer PL Terai K Molecular and cellular characterization of the membrane attack complex, C5b–9, in Alzheimer's disease Neurobiol Aging 1997 18 415 421 10.1016/s0197-4580(97)00042-0 9330973 · DOI
  15. [19]Maier M Peng Y Jiang L Seabrook TJ Carroll MC Lemere CA Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice J Neurosci 2008 28 6333 6341 10.1523/JNEUROSCI.0829-08.2008 18562603 PMC3329761 · DOI · Paper page
  16. [21]Stevens B Allen NJ Vazquez LE Howell GR Christopherson KS Nouri N The classical complement cascade mediates CNS synapse elimination Cell 2007 131 1164 1178 10.1016/j.cell.2007.10.036 18083105 · DOI · Paper page
  17. [22]Chu Y Jin X Parada I Pesic A Stevens B Barres B Enhanced synaptic connectivity and epilepsy in C1q knockout mice Proc Natl Acad Sci U S A 2010 107 7975 7980 10.1073/pnas.0913449107 20375278 PMC2867906 · DOI · Paper page
  18. [23]Sekar A Bialas AR de Rivera H Davis A Hammond TR Kamitaki N Schizophrenia risk from complex variation of complement component 4 Nature 2016 530 177 183 10.1038/nature16549 26814963 PMC4752392 · DOI · Paper page
  19. [25]Schafer DP Stevens B Synapse elimination during development and disease: immune molecules take centre stage Biochem Soc Trans 2010 38 476 481 10.1042/BST0380476 20298206 · DOI
  20. [26]Stephan AH Barres BA Stevens B The complement system: an unexpected role in synaptic pruning during development and disease Annu Rev Neurosci 2012 35 369 389 10.1146/annurev-neuro-061010-113810 22715882 · DOI · Paper page
  21. [27]Dalakas MC Alexopoulos H Spaeth PJ Complement in neurological disorders and emerging complement-targeted therapeutics Nat Rev Neurol 2020 16 601 617 10.1038/s41582-020-0400-0 33005040 PMC7528717 · DOI
  22. [28]Koopman JJE van Essen MF Rennke HG de Vries APJ van Kooten C Deposition of the membrane attack complex in healthy and diseased human kidneys Front Immunol 2020 11 599974 10.3389/fimmu.2020.599974 33643288 PMC7906018 · DOI
  23. [29]Fluiter K Opperhuizen AL Morgan BP Baas F Ramaglia V Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice J Immunol 2014 192 2339 2348 10.4049/jimmunol.1302793 24489093 · DOI
  24. [30]Mead RJ Singhrao SK Neal JW Lassmann H Morgan BP The membrane attack complex of complement causes severe demyelination associated with acute axonal injury J Immunol 2002 168 458 465 10.4049/jimmunol.168.1.458 11751993 · DOI
  25. [31]Morgan BP Chamberlain-Banoub J Neal JW Song W Mizuno M Harris CL The membrane attack pathway of complement drives pathology in passively induced experimental autoimmune myasthenia gravis in mice Clin Exp Immunol 2006 146 294 302 10.1111/j.1365-2249.2006.03205.x 17034582 PMC1942050 · DOI
  26. [32]Howard JF Jr Myasthenia gravis: the role of complement at the neuromuscular junction Ann N Y Acad Sci 2018 1412 113 128 10.1111/nyas.13522 29266249 · DOI
  27. [33]Botto M Dell'Agnola C Bygrave AE Thompson EM Cook HT Petry F Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies Nat Genet 1998 19 56 59 10.1038/ng0598-56 9590289 · DOI · Paper page
  28. [34]Holt DS Botto M Bygrave AE Hanna SM Walport MJ Morgan BP Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria Blood 2001 98 442 449 10.1182/blood.v98.2.442 11435315 · DOI
  29. [37]Tai HC Serrano-Pozo A Hashimoto T Frosch MP Spires-Jones TL Hyman BT The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system Am J Pathol 2012 181 1426 1435 10.1016/j.ajpath.2012.06.033 22867711 PMC3463637 · DOI
  30. [38]Byrne RAJ Torvell M Daskoulidou N Fathalla D Kokkali E Carpanini SM Novel monoclonal antibodies against mouse C1q: characterisation and development of a quantitative ELISA for mouse C1q Mol Neurobiol 2021 58 4323 4336 10.1007/s12035-021-02419-5 34002346 PMC8487419 · DOI
  31. [39]Zelek WM Morgan BP Monoclonal antibodies capable of inhibiting complement downstream of C5 in multiple species Front Immunol 2020 11 612402 10.3389/fimmu.2020.612402 33424866 PMC7793867 · DOI
  32. [40]Zelek WM Taylor PR Morgan BP Development and characterization of novel anti-C5 monoclonal antibodies capable of inhibiting complement in multiple species Immunology 2019 157 283 295 10.1111/imm.13083 31120547 PMC6620185 · DOI
  33. [41]Bevan RJ Hughes TR Williams PA Good MA Morgan BP Morgan JE Retinal ganglion cell degeneration correlates with hippocampal spine loss in experimental Alzheimer's disease Acta Neuropathol Commun 2020 8 216 10.1186/s40478-020-01094-2 33287900 PMC7720390 · DOI
  34. [42]Gan WB Grutzendler J Wong WT Wong RO Lichtman JW Multicolor "DiOlistic" labeling of the nervous system using lipophilic dye combinations Neuron 2000 27 219 225 10.1016/s0896-6273(00)00031-3 10985343 · DOI
  35. [43]Staffend NA Meisel RL DiOlistic labeling of neurons in tissue slices: a qualitative and quantitative analysis of methodological variations Front Neuroanat 2011 5 14 10.3389/fnana.2011.00014 21427781 PMC3049322 · DOI
  36. [44]Sun W Li N He S Large-scale morophological survey of rat retinal ganglion cells Vis Neurosci 2002 19 483 493 10.1017/s0952523802194107 12511081 · DOI
  37. [45]Zelek WM Measuring total classical pathway and activities of individual components of the mouse complement pathway Bio Protoc 2021 11 e4175 10.21769/BioProtoc.4175 34722822 PMC8517650 · DOI
  38. [46]Zelek WM Harris CL Morgan BP Extracting the barbs from complement assays: identification and optimisation of a safe substitute for traditional buffers Immunobiology 2018 223 744 749 10.1016/j.imbio.2018.07.016 30033110 · DOI
  39. [47]Mehla J Lacoursiere SG Lapointe V McNaughton BL Sutherland RJ McDonald RJ Age-dependent behavioral and biochemical characterization of single APP knock-in mouse (APP(NL-G-F/NL-G-F)) model of Alzheimer's disease Neurobiol Aging 2019 75 25 37 10.1016/j.neurobiolaging.2018.10.026 30508733 · DOI · Paper page
  40. [48]Xu J Patassini S Rustogi N Riba-Garcia I Hale BD Phillips AM Regional protein expression in human Alzheimer's brain correlates with disease severity Commun Biol 2019 2 43 10.1038/s42003-018-0254-9 30729181 PMC6361956 · DOI
  41. [49]Hesse R Hurtado ML Jackson RJ Eaton SL Herrmann AG Colom-Cadena M Comparative profiling of the synaptic proteome from Alzheimer's disease patients with focus on the APOE genotype Acta Neuropathol Commun 2019 7 214 10.1186/s40478-019-0847-7 31862015 PMC6925519 · DOI
  42. [50]Sanchez-Varo R Sanchez-Mejias E Fernandez-Valenzuela JJ De Castro V Mejias-Ortega M Gomez-Arboledas A Plaque-associated oligomeric amyloid-beta drives early synaptotoxicity in APP/PS1 mice hippocampus: ultrastructural pathology analysis Front Neurosci 2021 15 752594 10.3389/fnins.2021.752594 34803589 PMC8600261 · DOI
  43. [51]Stevens B Johnson MB The complement cascade repurposed in the brain Nat Rev Immunol 2021 21 624 625 10.1038/s41577-021-00621-z 34580464 · DOI
  44. [52]Gyorffy BA Kun J Torok G Bulyaki E Borhegyi Z Gulyassy P Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning Proc Natl Acad Sci U S A 2018 115 6303 6308 10.1073/pnas.1722613115 29844190 PMC6004452 · DOI
  45. [53]Kovacs RA Vadaszi H Bulyaki E Torok G Toth V Matyas D Identification of neuronal pentraxins as synaptic binding partners of C1q and the involvement of NP1 in synaptic pruning in adult mice Front Immunol 2020 11 599771 10.3389/fimmu.2020.599771 33628204 PMC7897678 · DOI · Paper page
  46. [54]Scott-Hewitt N Perrucci F Morini R Erreni M Mahoney M Witkowska A Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia EMBO J 2020 39 e105380 10.15252/embj.2020105380 32657463 PMC7429741 · DOI
  47. [55]Neumann H Kotter MR Franklin RJ Debris clearance by microglia: an essential link between degeneration and regeneration Brain 2009 132 288 295 10.1093/brain/awn109 18567623 PMC2640215 · DOI · Paper page
  48. [56]Weinhard L di Bartolomei G Bolasco G Machado P Schieber NL Neniskyte U Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction Nat Commun 2018 9 1228 10.1038/s41467-018-03566-5 29581545 PMC5964317 · DOI · Paper page
  49. [57]Sahashi K Engel AG Lambert EH Howard FM Jr Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis J Neuropathol Exp Neurol 1980 39 160 172 10.1097/00005072-198003000-00005 7373347 · DOI
  50. [58]Chamberlain-Banoub J Neal JW Mizuno M Harris CL Morgan BP Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats Clin Exp Immunol 2006 146 278 286 10.1111/j.1365-2249.2006.03198.x 17034580 PMC1942064 · DOI
  51. [59]Wu T Dejanovic B Gandham VD Gogineni A Edmonds R Schauer S Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy Cell Rep 2019 28 2111–2123 e2116 10.1016/j.celrep.2019.07.060 31433986 · DOI · Paper page
  52. [60]Zhou J Fonseca MI Pisalyaput K Tenner AJ Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease J Neurochem 2008 106 2080 2092 10.1111/j.1471-4159.2008.05558.x 18624920 PMC2574638 · DOI
  53. [61]Shen Y Li R McGeer EG McGeer PL Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain Brain Res 1997 769 391 395 10.1016/s0006-8993(97)00850-0 9374212 · DOI
  54. [62]Yu JX Bradt BM Cooper NR Constitutive expression of proinflammatory complement components by subsets of neurons in the central nervous system J Neuroimmunol 2002 123 91 101 10.1016/s0165-5728(01)00483-0 11880154 · DOI
  55. [63]Xie J Gorle N Vandendriessche C Van Imschoot G Van Wonterghem E Van Cauwenberghe C Low-grade peripheral inflammation affects brain pathology in the App(NL-G-F)mouse model of Alzheimer's disease Acta Neuropathol Commun 2021 9 163 10.1186/s40478-021-01253-z 34620254 PMC8499584 · DOI
  56. [64]Staffend NA, Meisel RL (2011) DiOlistic labeling in fixed brain slices: phenotype, morphology, and dendritic spines. Curr Protoc Neurosci Chapter 2: Unit 2 13 Doi 10.1002/0471142301.ns0213s55 PMC3072225 21462159 · DOI
  57. [65]Arendt T Synaptic degeneration in Alzheimer's disease Acta Neuropathol 2009 118 167 179 10.1007/s00401-009-0536-x 19390859 · DOI · Paper page
  58. [67]Xu B Sun A He Y Qian F Xi S Long D Loss of thin spines and small synapses contributes to defective hippocampal function in aged mice Neurobiol Aging 2018 71 91 104 10.1016/j.neurobiolaging.2018.07.010 30118927 · DOI
  59. [68]Duan T Smith AJ Verkman AS Complement-dependent bystander injury to neurons in AQP4-IgG seropositive neuromyelitis optica J Neuroinflammation 2018 15 294 10.1186/s12974-018-1333-z 30348195 PMC6198534 · DOI
  60. [69]Morgan BP The membrane attack complex as an inflammatory trigger Immunobiology 2016 221 747 751 10.1016/j.imbio.2015.04.006 25956457 · DOI · Paper page
  61. [70]Triantafilou K Hughes TR Triantafilou M Morgan BP The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation J Cell Sci 2013 126 2903 2913 10.1242/jcs.124388 23613465 · DOI
  62. [71]Albazli K Kaminski HJ Howard JF Jr Complement inhibitor therapy for myasthenia gravis Front Immunol 2020 11 917 10.3389/fimmu.2020.00917 32582144 PMC7283905 · DOI
  63. [72]Pittock SJ Berthele A Fujihara K Kim HJ Levy M Palace J Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder N Engl J Med 2019 381 614 625 10.1056/NEJMoa1900866 31050279 · DOI
  64. [74]Montagne A Zhao Z Zlokovic BV Alzheimer's disease: A matter of blood-brain barrier dysfunction? J Exp Med 2017 214 3151 3169 10.1084/jem.20171406 29061693 PMC5679168 · DOI · Paper page
  65. [75]Profaci CP Munji RN Pulido RS Daneman R The blood-brain barrier in health and disease: important unanswered questions J Exp Med 2020 10.1084/jem.20190062 32211826 PMC7144528 · DOI
  66. [76]Sweeney MD Sagare AP Zlokovic BV Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders Nat Rev Neurol 2018 14 133 150 10.1038/nrneurol.2017.188 29377008 PMC5829048 · DOI · Paper page
  67. [77]Wang D Chen F Han Z Yin Z Ge X Lei P Relationship between amyloid-beta deposition and blood-brain barrier dysfunction in Alzheimer's disease Front Cell Neurosci 2021 15 695479 10.3389/fncel.2021.695479 34349624 PMC8326917 · DOI
  68. [78]Zelek WM Morgan BP Targeting complement in neurodegeneration challenges risks and strategies Trends Pharmacol Sci 2022 10.1016/j.tips.2022.02.006 35272861 · DOI

Cited by

Sorted by citations

Authors
Carpanini, S. M., Torvell, M., Bevan, R. J., Byrne, R. A. J., Daskoulidou, N., Saito, T., Saido, T. C., Taylor, P. R., Hughes, T. R., Zelek, W. M., & Morgan, B. P.
Affiliations
  • UK Dementia Research Institute (GB)
  • Nagoya City University (JP)
  • RIKEN Center for Brain Science (JP)
Corresponding author
Morgan, B. Paul
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2022-07-06
Volume
10
Issue
1
Pages
99-99
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-022-01404-w
PMC
PMC9258209
OpenAlex
W4283826758
Cited by
95
References
10
Citations by year
2026: 25 · 2025: 26 · 2024: 28 · 2023: 16
FWCI
11.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
UK Dementia Research Institute
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, complement system, membrane attack complex, synaptic loss, C1q, C3 fragments, C7, C6, 3xTg-AD mice, dendritic spines, amyloid plaques, microglial phagocytosis, synaptoneurosomes, complement dysregulation
MeSH terms
Alzheimer Disease, Animals, Complement System Proteins, Complement Activation, Synapses, Complement C1q, Complement Membrane Attack Complex, Mice, Plaque, Amyloid

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