Skip to main content
Log in

Complement activation in amyloid plaques in Alzheimer's disease brains does not proceed further than C3

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

In Alzheimer's disease (AD) patients, the complement components Clq, C4 and C3 can be detected in different types of β/A4 plaques, one of the hallmarks of AD. Contradictory findings on the presence of late complement components in AD brains have been reported. Nevertheless, it was suggested in recent studies that in AD brain complement activation results in complement membrane attack complex (MAC) formation and that complement activation may act as an intermediate between β/A4 deposits and the neurotoxicity observed in AD. In the present study the presence of a number of complement components and regulatory proteins in AD temporal cortex and, for comparison, in glomerulone-phritis (GN) was analysed. In GN kidneys, besides Clq, Clr, Cls and C3, the late components and the C5b-9 complex are also associated with capillary basement membrane and mesangial immune complex deposits. In AD temporal cortex Clq, C4 and C3 are co-localized with β/A4 deposits. However, in contrast to the GN kidney, the late complement components C5, C7 and C9, as well as the C5b-9 membrane attack complex cannot be detected in β/A4 positive plaques. The absence of the cytolytic C5b-9 complex in AD brain suggests that in AD, the complement MAC does not function as the proposed inflammatory mediator between β/A4 deposits and the neurofibrillary changes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Baatrup G, Svehag S-E, Jensenius JC (1986) The attachment of serum- and plasma-derived C3 to solid-phase immune aggregates and its relation to complement-mediated solubilization of immune complexes. Scand J Immunol 23:397–406

    Google Scholar 

  2. Bariety J, Hinglais N, Bhakdi S, Mandet C, Rouchon M, Kazatchkine MD (1989) Immunohistochemical study of complement S protein (vitronectin) in normal and diseased human kidneys: relationship to neoantigens of the C5b-9 terminal complex. Clin Exp Immunol 75:76–81

    Google Scholar 

  3. Bhakdi S, Muhly M, Roth M (1983) Preparation and isolation of specific antibodies to complement components. Methods Enzymol 93:409–420

    Google Scholar 

  4. Biesecker G (1990) The complement C5b-9 complex mediates cell adhesion through a vitronectin receptor. J Immunol 145:209–214

    Google Scholar 

  5. Biesecker G, Katz S, Koffler D (1981) Renal localization of the membrane attack complex in systemic lupus erythematosus nephritis. J Exp Med 154:1779–1794

    Google Scholar 

  6. Delaère P, Duyckaerts C, He Y, Piette F, Hauw JJ (1991) Subtypes and differential laminar distributions of βA4 deposits in Alzheimer's disease: relationship with intellectual status of 26 cases. Acta Neuropathol (Berl) 81:328–335

    Google Scholar 

  7. Eikelenboom P, Stam FC (1982) Immunoglobulins and complement factors in senile plaques. An histochemical study. Acta Neuropathol (Berl) 57:239–242

    Google Scholar 

  8. Eikelenboom P, Stam FC (1984) An histochemical study on cerebral vascular and senile plaque amyloid in Alzheimer's disease. Virchows Arch [B] 47:17–25

    Google Scholar 

  9. Eikelenboom P, Hack CE, Rozemuller JM, Stam FC (1989) Complement activation in amyloid plaques in Alzheimer's dementia. Virchows Arch [B] 56:259–262

    Google Scholar 

  10. Eikelenboom P, Rozemuller JM, Kraal G, Stam FC, McBride PA, Bruce ME, Fraser H (1991) Cerebral amyloid plaques in Alzheimer's disease but not in scrapie-affected mice are closely associated with a local inflammatory process. Virchows Arch [B] 60:329–336

    Google Scholar 

  11. Eikelenboom P, Hack CE, Kamphorst W, Rozemuller JM (1992) Distribution pattern and functional state of complement proteins and α1-antichymotrypsin in cerebral β/A4 deposits in Alzheimer's disease. Res Immunol 143:617–620

    Google Scholar 

  12. Gasque P, Ischenko A, Legoedec J, Mauger C, Schouft M-T, Fontaine M (1993) Expression of the complement classical pathway by human glioma in culture. J Biol Chem 268:25068–25074

    Google Scholar 

  13. Gewurz H, Ying S-C, Jiang H, Flint TF (1993) Nonimmune activation of the classical complement pathway. Behring Inst Mitt 93:138–147

    Google Scholar 

  14. Ghebrehiwet B, Habicht GS, Beck G (1990) Interaction of Clq with its receptor on cultured cell lines induces an anti-proliferative response. Clin Immunol Immunopathol 54:148–160

    Google Scholar 

  15. Ishii T, Haga S (1984) Immuno-electron microscopic localization of complements in amyloid fibrils of senile plaques. Acta Neuropathol (Berl) 63:296–300

    Google Scholar 

  16. Ishii T, Haga S, Kametani F (1988) Presence of immunoglobulins and complements in the amyloid plaques in the brain of patients with Alzheimer's disease. In: Pouplard-Barthelaix A, Emile J, Christen Y (eds) Immunology and Alzheimer's disease. Springer, Berlin Heidelberg New York, pp 17–29

    Google Scholar 

  17. Itagaki S, Akiyama H, Saito H, McGeer PL (1994) Ultrastructural localization of complement membrane attack complex (MAC)-like immunoreactivity in brains of patients with Alzheimer's disease. Brain Res 645:78–84

    Google Scholar 

  18. Jenne DE, Stanley KK (1985) Molecular cloning of S-protein, a link between complement, coagulation and cell substrate adhesion. EMBO J 4:3153–3157

    Google Scholar 

  19. Jenne DE, Tschopp J (1992) Clusterin: the intriguing guises of a widely expressed glycoprotein. Trends Biol Sci 17:154–159

    Google Scholar 

  20. Jiang H, Burdick D, Glabe CG, Cotman CWE, Tenner AJ (1994) β-Amyloid activates complement by binding to a specific region of the collagen-like domain of the Clq A chain. J Immunol 152:5050–5059

    Google Scholar 

  21. Johnson SA, Lampert-Etchells M, Pasinetti GM, Rozovsky I, Finch CE (1992) Complement mRNA in the mammalian brain: responses to Alzheimer's disease and experimental brain lesioning. Neurobiol Aging 13:641–648

    Google Scholar 

  22. Kalaria RN (1993) The immunopathology of Alzheimer's disease and some related disorders. Brain Pathol 3:333–347

    Google Scholar 

  23. Kemp PA, Spragg JH, Brown JC, Morgan BP, Gunn C, Taylor PW (1992) Immunohistochemical determination of complement activation in joint tissues of patients with rheumatoid arthritis and osteoarthritis using neoantigen-specific monoclonal antibodies. J Clin Lab Immunol 37:147–162

    Google Scholar 

  24. Lachmann PJ (1991) The control of homologous lysis. Immunol Today 12:312–315

    Google Scholar 

  25. Leu RW, Stewart CA, Herriott MJ, Fast DJ, Rummage JA (1993) Inhibitor of Clq secretion suppresses the macrophage response to lipid A for nitric oxide but not for TNF production: Evidence for a role of Clq in autocrine binding of TNF. Immunobiology 188:242–258

    Google Scholar 

  26. May PC, Finch CE (1992) Sulphated glycoprotein-2: new relationship of this multifunctional protein to neurodegeneration. Trends Neurosci 15:391–396

    Google Scholar 

  27. McDonald B, Esiri MM, McIlhinney RAJ (1991) A monoclonal antibody that reacts immunohistochemically with amyloid deposits in the brain tissue of Alzheimer patients binds to an epitope present on complement factor 4. J Neurochem 57:1172–1177

    Google Scholar 

  28. McGeer PL, McGeer EG (1992) Complement proteins and complement inhibitors in Alzheimer's disease. Res Immunol 143:621–624

    Google Scholar 

  29. McGeer PL, Akiyama H, Itagaki S, McGeer EG (1989) Immune system response in Alzheimer's disease. Can J Neurol Sci 16:516–527

    Google Scholar 

  30. Mollnes TE, Lea T, Harboe M, Tschopp J (1985) Monoclonal antibodies recognizing a neoantigen of poly (C9) detect human terminal complement complex in tissue and plasma. Scand J Immunol 22:183–195

    Google Scholar 

  31. Morgan BP, Draw RA, Siddle K, Luzio JP, Campbell AK (1983) Immunoaffinity purification of human complement C9 using monoclonal antibodies. J Immunol Methods 64:269–281

    Google Scholar 

  32. Okada M, Yoshioka K, Takemura T, Akano N, Aya N, Murakami K, Maki S (1993) Immunohistochemical localization of C3d fragment of complement and S-protein (vitronectin) in normal and diseased human kidneys: association with the C5b-9 complex and vitronectin receptor. Virchows Arch 422:367–373

    Google Scholar 

  33. Pasinetti GM, Johnson SA, Rozovsky I, Lampert-Etchells M, Morgan DG, Gordon MN, Willoughby D, Finch CE (1992) Complement ClqB and C4 mRNAs responses to lesioning in rat brain. Exp Neurol 118:117–125

    Google Scholar 

  34. Pouplard-Barthelaix A (1988) Immunological markers and neuropathological lesions in Alzheimer's disease. In: Pouplard-Barthelaix A, Emile J, Christen Y (eds) Immunology and Alzheimer's disease. Springer, Berlin Heidelberg New York, pp 7–16

    Google Scholar 

  35. Rogers J, Schultz J, Brachova L, Lue L-F, Webster S, Bradt B, Cooper NR, Moss DE (1992) Complement activation and β-amyloid-mediated neurotoxicity in Alzheimer's disease. Res Immunol 143:624–630

    Google Scholar 

  36. Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, Civin WH, Brachova L, Bradt B, Ward P, Lieberburg I (1992) Complement activation by β-amyloid in Alzheimer disease. Proc Natl Acad Sci 89:10016–10020

    Google Scholar 

  37. Rosenblatt DE, Geula C, Mesulam M-M (1989) Protease nexin I immunostaining in Alzheimer's disease. Ann Neurol 26:628–634

    Google Scholar 

  38. Rozemuller JM, Eikelenboom P, Pals ST, Stam FC (1989) Microglial cells around amyloid plaques in Alzheimer's disease express leucocyte adhesion molecules of the LFA-1 family. Neurosci Lett 101:288–292

    Google Scholar 

  39. Rozemuller JM, Eikelenboom P, Stam FC, Beyreuther K, Masters CL (1989) A4 protein in Alzheimer's disease: primary and secundary cellular events in extracellular amyloid deposition. J Neuropathol Exp Neurology 48:674–691

    Google Scholar 

  40. Selkoe DJ (1993) Physiological production of the β-amyloid protein and the mechanism of Alzheimer's disease. Trends Neurosci 16:403–409

    Google Scholar 

  41. Sim RB, Reid KBM (1991) C1: molecular interactions with activating systems. Immunol Today 12:307–311

    Google Scholar 

  42. Van Nostrand WE, McKay LD, Baker JB, Cunningham DD (1988) Functional and structural similarities between protease nexin I and C1 Inhibitor. J Biol Chem 263:3979–3983

    Google Scholar 

  43. Wagner SL, Geddes JW, Cotman CW, Lau AL, Gurwitz D, Isackson PJ, Cunningham DD (1989) Protease nexin-1, an antithrombin with neurite outgrowth activity, is reduced in Alzheimer's disease. Proc Natl Acad Sci 86:8284–8288

    Google Scholar 

  44. Wagner SL, Van Nostrand WE, Lau AL, Farrow JS, Suzuki M, Bartus RT, Schuppek R, Nguyen A, Cotman CW, Cunningham DD (1993) Co-distribution of protease nexin-1 and protease nexin-2 in brains of non-human primates. Brain Res 626:90–98

    Google Scholar 

  45. Walker DG, McGeer PL (1993) Complement gene expression in neuroblastoma and astrocytoma cell lines of human origin. Neurosci Lett 157:99–102

    Google Scholar 

  46. Webster SD, Rogers J (1993) Acceleration of β-amyloid peptide aggregation by Clq. Society for Neuroscience Abstracts 19:19

    Google Scholar 

  47. Zhan S-S, Veerhuis R, Janssen I, Kamphorst W, Eikelenboom P (1994) Distribution of the inhibitors of the terminal complement complex in Alzheimer's disease brain. Neurodegeneration 3:111–117

    Google Scholar 

  48. Ziccardi RJ (1982) A new role for C1-Inhibitor in homeostasis: control of activation of the first component of human complement. J Immunol 128:2505–2508

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Veerhuis, R., van der Valk, P., Janssen, I. et al. Complement activation in amyloid plaques in Alzheimer's disease brains does not proceed further than C3. Vichows Archiv A Pathol Anat 426, 603–610 (1995). https://doi.org/10.1007/BF00192116

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00192116

Key words

Navigation