Skip to main content
SpringerLink
Log in

Cerebral amyloid plaques in Alzheimer’s disease but not in scrapie-affected mice are closely associated with a local inflammatory process

  • Published:
Virchows Archiv B

Summary

Complement proteins of the classical pathway can be immunohistochemically identified in cerebral amyloid plaques in Alzheimer’s disease. Microglial cells in and around amyloid plaques express class II major histocompatibility (MHC) antigens and complement receptors CR3 and CR4. Negative immunostaining for immunoglobulins and for T-cell subsets in the brain parenchyma demonstrates a lack of evidence for the involvement of specific immune responses (such as an immune complex-mediated complement activation or a cell-mediated immune response) in cerebral amyloid deposits in Alzheimer’s disease. Cerebral amyloid plaques in scrapie-affected mice (slow-virus induced encephalopathy) do not contain complement factors C1q and C3c and are not clustered with microglial cells expressing MHC class II molecules or complement receptor CR3. The data presented suggest the induction of a reactive inflammatory process by β/A4 amyloid in the human brain, but not by scrapie-induced PrP amyloid in mice. Our findings do not support the hypothesis that the immune system is involved in the generation of amyloid plaques in Alzheimer’s disease.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abraham CR, Selkoe DJ, Potter H (1988) Immunochemical identification of the serine protease inhibitor α1-antichymotrypsin in the brain amyloid deposits of Alzheimer’s disease. Cell 52:487–501

    Article  PubMed  CAS  Google Scholar 

  • Abraham CR, Potter H (1989) Alzheimer’s disease: recent advances in understanding the brain amyloid deposits. Biotechnology 7:147–153

    Article  CAS  Google Scholar 

  • Alafuzoff I, Adolfsson R, Grundke-Iqbal I, Winblad B (1987) Blood-brain barrier in Alzheimer dementia and in nondemented elderly. Acta Neuropathol (Berl) 73:160–166

    Article  CAS  Google Scholar 

  • Bhattacharya A, Dorf ME, Springer TA (1981) A shared allogeneic determinant on Ia antigens encoded by the I-A and I-E subregion: evidence for a region gene duplication. J Immunol 127:2488

    PubMed  CAS  Google Scholar 

  • Boellaard JW, Schlote W (1981) Glial plaques: amyloid deposits characteristic of slow transmissible encephalopaties. Virchows Arch[B] 37:337–341

    Article  CAS  Google Scholar 

  • Bruce ME, Fraser H (1975) Amyloid plaques in the brains of mice infected with scrapie: Morphological variation and staining properties. Neuropathol Appl Neurobiol 1:189–202

    Google Scholar 

  • Bruce ME, Dickinson AG, Fraser H (1976) Cerebral amyloidosis in scrapie mouse-effect of agent strain and mouse genotype. Neuropathol Appl Neurobiol 2:471–478

    Google Scholar 

  • Cooper NR (1985) The classical complement pathway: activation and regulation of the first complement component. Adv Immunol 37:151–216

    PubMed  CAS  Google Scholar 

  • Coria F, Castano E, Prelli F, Larrondo-Lilli M, van Duinen S, Shelanski ML, Frangione B (1988) Isolation and characterization of amyloid P-component from Alzheimer’s disease and other cerebral amyloidosis. Lab Invest 58:454–458

    PubMed  CAS  Google Scholar 

  • Dustin ML, Rothlein R, Bhan AR, Dinarello CA, Springer TA (1986) Induction by IL-1 and interferon, tissue distribution, biochemistry and function of a natural adherance molecule (ICAM-1). J Immunol 137:245–254

    PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Eikelenboom P, Scott JR, McBride PA, Rozemuller JM, Bruce ME, Fraser H (1987) No evidence for involvement of plasma proteins or blood-borne cells in amyloid plaque formation in scrapie-affected mice. An immunohistoperoxidase study Virchows Arch [B] 53:251–256

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Evans RL, Wall DW, Platsoucas CD, Siegal FP, Fikrig SM, Testa CM, Good RA (1981) Thymus dependent membrane antigens in man: Inhibition of cell-mediated lympholysis by monoclonal antibodies to the TH2 antigen. Proc Natl Acad Sci USA 78:544–548

    Article  PubMed  CAS  Google Scholar 

  • Gerdes J, Naiem M, Masson DY, Stein H (1982) Human complement (C3b) receptors defined by as mouse monoclonal antibody. Immunology 45:645–653

    PubMed  CAS  Google Scholar 

  • Glenner GG, Wong CW (1984) Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890

    Article  PubMed  CAS  Google Scholar 

  • Goldgaber D, Harris HW, Hla T, Maciag T, Donelly RJ, Jacobson JS, Vitek MP, Gajdusek DC (1989) Interleukin 1 regulates synthesis of amyloid B-protein precursor mRNA in human endothelial cells. Proc Natl Acad Sci USA 86:7606–7610

    Article  PubMed  CAS  Google Scholar 

  • Griffin WST, Stanley LC, Ling C, White L, Macleod V, Perrot LC, White CL, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 86:7611–7615

    Article  PubMed  CAS  Google Scholar 

  • Hack CE, Paardekoper J, Smeenk RJT, Abbink J, Eerenberg AJM, Nuyens JH (1988) Disruption of the internal thioexter bond of the third component of the complement (C3) results in the exposure of neodeterminants also present on activation products of C3. J Immunol 141:1602–1609

    PubMed  CAS  Google Scholar 

  • Hsu SM, Soban E (1982) Color modification of diaminobenzidine (DAB) precipitation by metallic ions and its application for double immonohistochemistry. J Histochem Cytochem 30:1079–1082

    PubMed  CAS  Google Scholar 

  • Ikeda SI, Allsop D, Glenner GG (1989) Morphology and distribution of plaque and related deposits in the brains of Alzheimer’s disease and control cases. Lab Invest 60:113–119

    PubMed  CAS  Google Scholar 

  • Ishii T, Haga S, Shimizu F (1975) Identification of components of immunoglobulins in senile plaques by means of fluorescent antibody technique. Acta Neuropathol (Berl) 32:157–162

    Article  CAS  Google Scholar 

  • Ishii T, Haga S (1976) Immuno-electron microscopic localization of immunoglobulins in amyloid fibrils of senile plaques. Acta Neuropathol (Berl) 36:243–249

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Ishii T, Haga S, Kametani F (1988) Presence of immunoglobulins and complements 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 Tokyo, pp 17–29

    Google Scholar 

  • Itagaki S, McGeer PL, Akiyama H (1988) Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer’s disease brain tissue. Neurosci Lett 91:259–264

    Article  PubMed  CAS  Google Scholar 

  • Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D (1989) Relationships of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 24:173–182

    Article  PubMed  CAS  Google Scholar 

  • Joachim CL, Morris J, Selkoe DJ (1989) Diffuse senile plaques occur commonly in the cerebellum in Alzheimer’s disease. Am J Pathol 135:309–319

    PubMed  CAS  Google Scholar 

  • Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grezschik K-H, Multhaup G, Beyreuther K, Müller-Hill B (1987) The precursor of Alzheimer’s disease amyloid β/A4 protein resembles a cell-surface receptor. Nature 325:733–736

    Article  PubMed  CAS  Google Scholar 

  • Keizer GD, Borst J, Frigdor CG, Spits H, Miedema F, Terhorst C, De Vries JE (1985) Biochemical and functional characteristics of the human leucocyte membrane antigen family LFA-1, Mo-1 and P150,95. Eur J Immunol 15:1142–1147

    Article  PubMed  CAS  Google Scholar 

  • Kishimoto T, Larson RS, Corbi AL, Dustin ML, Staunton DE, Springer TA (1989) The leucocyte integrins. Adv Immunol 46:149–182

    PubMed  CAS  Google Scholar 

  • Kretzschmar HA, Prusiner SB, Stowring LE, de Armond SJ (1986) Scrapie prion proteins are synthesized in neurons. Am J Pathol 122:1–5

    PubMed  CAS  Google Scholar 

  • Ledbetter JA, Herzenberg LA (1979) Xenogeneic monoclonal antibodies to mouse lymphoid differentation antigens. Immunol Rev 47:63–90

    Article  PubMed  CAS  Google Scholar 

  • Mann DMA, Davies JS, Hawkes JE, Yates PO (1982) Immunohistochemical staining of senile plaques. Neuropathol Appl Neurobiol 8:55–61

    PubMed  CAS  Google Scholar 

  • Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245–4249

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto Y, Watenabe K, Ikuta F (1985) Immunohistochemical study on neuroglia, identified by the monoclonal antibodies against a macrophage differentiation antigen (Mac 1). J Neuroimmunol 9:379–389

    Article  PubMed  CAS  Google Scholar 

  • Miedema F, Tettero PT, Hesselink WG, Werner G, Spits H, Melief CJM (1984) Both Fc receptors and lymphocyte-function-associated antigen-1 on human lymphocytes are required for antibody-dependent cytoxicity (killer cell activity). Eur J Immunol 14:518–523

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79:195–200

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, Akiyama H, Itagaki S, McGeer EG (1989a) Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett 107:341–346

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Pierres M, Goridis C, Golstein P (1982) Inhibition of murine T cell mediated cytolysis and T cell proliferation by a rat monoclonal antibody immunoprecipitating two lymphoid cell surface polypeptides of 94.000 and 180.000 molecular weight. Eur J Immunol 12:60–69

    Article  PubMed  CAS  Google Scholar 

  • Pierres A, Nagnet P, Van Agthoven A, Bekkhoucha F, Denizot F, Mishal Z, Smit-Verhulst AM, Pierres M (1984) A rat anti mouse T4 monoclonal antibody H129.19 inhibits the proliferation of Ia-reactive T cell clones and delineates two phenotypically distinct (T4+, Lyt-2, 3- and T-4-, Lyt-2,3+) subsets among anti-Ia cytolytic T cells clones. J Immunol 132:2775–2782

    PubMed  CAS  Google Scholar 

  • Pouplard A, Emile J (1985) New immunological findings in senile dementia. Interdis Top Gerontol 19:62–71

    Google Scholar 

  • Pouplard-Barthelaix A, Dubas F, Jabbour W, Maher I, Emile J (1986) An immunological view on the etiology and pathogenesis of Alzheimer’s disease. In: Bes A (ed) Senile dementia early detection. John Libbey Eurotext, Paris, pp 216–222

    Google Scholar 

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

    Google Scholar 

  • Powers JM, Schlaepfer WW, Willingham MC, Hall BJ (1981) An immunoperoxidase study of senile cerebral amyloidosis with pathogenetic considerations. J Neuropathol Exp Neurol 49:592–612

    Google Scholar 

  • Puchtler H, Swart F, Levine M (1962) On the binding of Congo red by amyloid. J Histochem Cytochem 10:355–364

    CAS  Google Scholar 

  • Reinherz EL, Kung PC, Pesando JM, Ritz J, Goldstein G, Schlossman SF (1979) Ia determinants on human T-cell subsets defined by monoclonal antibody activation stimuli required for expression. J Exp Med 150:1472–1482

    Article  PubMed  CAS  Google Scholar 

  • Roberts GW, Lofthouse R, Brown R, Crow TJ, Barry RA, Prusiner SB (1986) Prion-protein immuno-reactivity in human transmissible dementia. New Engl J Med 315:1231–1232

    CAS  Google Scholar 

  • Rogers J, Luber-Narod J, Styzen SD, Civin WH (1988) Expression of immune system-associated antigen by cells of the human central nervous system. Relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9:330–349

    Google Scholar 

  • Rozemuller JM, Eikelenboom P, Kamphorst W, Stam FC (1988) Lack of evidence for dysfunction of the blood-brain barrier in Alzheimer’s disease. An immunohistochemical study. Neurobiol Aging 9:383–391

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Rozemuller JM, Eikelenboom P, Stam FC, Beyreuther K, Masters CL (1989 b) A4 protein in Alzheimer’s disease, primary and secondary cellular events in extracellular amyloid deposition. J Neuropathol Exp Neurol 48:647–663

    Google Scholar 

  • Salbaum JM, Masters CL, Beyreuther K (1989) The amyloid gene of Alzheimer’s disease and neuronal dysfunction. In: Boller F, Katzman R, Rascol A, Signal JL, Christen Y (eds) Biological markers of Alzheimer’s disease. Springer, Berlin Heidelberg New York Tokyo, pp 118–122

    Google Scholar 

  • Schwarting R, Stein H, Wang CY (1985) The monoclonal antibodies αS-HCL1 (αLeu-14) and αS-HCL3 (αLeu M5) allow the diagnosis of hairy cell leukemia. Blood 65:974–983

    PubMed  CAS  Google Scholar 

  • Selkoe DJ, Abraham CR, Podlisny MB, Duffy LK (1986) Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer’s disease. J Neurochem 46:1820–1834

    PubMed  CAS  Google Scholar 

  • Springer T, Galfri GD, Secher DS, Milstein C (1979) Mac-1: a macrophage differentation antigen identified by monoclonal antibody. Eur J Immunol 9:301–306

    Article  PubMed  CAS  Google Scholar 

  • Stam FC (1965) Histochemistry in the senile evolution of the brain. In: Lüthy F, Bischoff A (eds) Proceedings of the Fifth International Congress of Neuropathology, Rome. Excerpta Medica Foundation, Amsterdam, pp 513–517

    Google Scholar 

  • Stam FC, Eikelenboom P (1985) Immunopathological study of cerebral senile amyloid (congophilic angiopathy and senile plaques). Interdis Top Gerontol 19:127–130

    Google Scholar 

  • Tagliavini F, Giaccone G, Frangione B, Bugiani O (1988) Preamyloid deposits in the cerebral cortex of patients with Alzheimer’s disease and nondemented individuals. Neurosci Lett 93:191–196

    Article  PubMed  CAS  Google Scholar 

  • Tedder TF, Clement LT, Cooper MD (1984) Expression of C3d receptors during human B cell differentiation: Immunofluorescence analysis with the HB-5 monoclonal antibody. J Immunol 133:678–683

    PubMed  CAS  Google Scholar 

  • Wegiel W, Wisniewski HM (1990) The complex of microglial cells and amyloid star in three-dimensional reconstruction. Acta Neuropathol (Berl) 81:116–124

    Article  CAS  Google Scholar 

  • Yamaguchi H, Hirai S, Morimatsu M, Shoji M, Ihara Y (1988) A variety of cerebral amyloid deposits in the brains of the Alzheimer-type dementia demonstrated by β-protein immunostaining. Acta Neuropathol (Berl) 76:541–549

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Psychiatry, Medical Faculty, Free University, Amsterdam, The Netherlands

    P. Eikelenboom

  2. Departments of Neuropathology, Medical Faculty, Free University, Amsterdam, The Netherlands

    J. M. Rozemuller & F. C. Stam

  3. Departments of Cell Biology, Medical Faculty, Free University, Amsterdam, The Netherlands

    G. Kraal

  4. Neuropathogenesis Unit, AFRC & MRC, West Mains Road, Edinburgh, UK

    P. A. McBride, M. E. Bruce & H. Fraser

Authors
  1. P. Eikelenboom
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. M. Rozemuller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Kraal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. C. Stam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. A. McBride
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. E. Bruce
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. Fraser
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This study was partly supported by a grant from the Praeventiefonds, project 28–1945

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eikelenboom, P., Rozemuller, J.M., Kraal, G. et al. Cerebral amyloid plaques in Alzheimer’s disease but not in scrapie-affected mice are closely associated with a local inflammatory process. Virchows Archiv B Cell Pathol 60, 329–336 (1991). https://doi.org/10.1007/BF02899564

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02899564

Key words

Search

Navigation