Skip to main content
SpringerLink
Log in

Siglec receptors and hiding plaques in Alzheimer's disease

Journal of Molecular Medicine Aims and scope Submit manuscript

Cite this article

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease. One hallmark of this disease is the continuous increase in the numbers and size of aggregating amyloid plaques. The accumulation of extracellular plaques is an immunologically interesting phenomenon since microglial cells, brain-specific macrophages, should be able to cleanse the aggregating material from the human brain. Immunotherapy targeting β-amyloid peptides in plaques with antibodies represents a promising therapy in AD. Recent progress in pattern recognition receptors of monocytes and macrophages has revealed that the sialic acid-binding, immunoglobulin-like lectin (Siglec) family of receptors is an important recognition receptor for sialylated glycoproteins and glycolipids. Interestingly, recent studies have revealed that microglial cells contain only one type of Siglec receptors, Siglec-11, which mediates immunosuppressive signals and thus inhibits the function of other microglial pattern recognition receptors, such as TLRs, NLRs, and RAGE receptors. We will review here the recent literature which clearly indicates that aggregating amyloid plaques are masked in AD by sialylated glycoproteins and gangliosides. Sialylation and glycosylation of plaques, mimicking the cell surface glycocalyx, can activate the immunosuppressive Siglec-11 receptors, as well as hiding the neuritic plaques, allowing them to evade the immune surveillance of microglial cells. This kind of immune evasion can prevent the microglial cleansing process of aggregating amyloid plaques in AD.

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

Fig. 1

Similar content being viewed by others

References

  1. Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81:741–766

    PubMed  CAS  Google Scholar 

  2. Farfara D, Lifshitz V, Frenkel D (2008) Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease. J Cell Mol Med 12:762–780

    Article  PubMed  CAS  Google Scholar 

  3. Armstrong RA (1998) Beta-amyloid plaques: stages in life history or independent origin. Dement Geriatr Cogn Disord 9:227–238

    Article  PubMed  CAS  Google Scholar 

  4. Guillozet AL, Weintraub S, Mash DC, Mesulam MM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60:729–736

    Article  PubMed  Google Scholar 

  5. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  PubMed  CAS  Google Scholar 

  6. D'Andrea MR, Cole GM, Ard MD (2004) The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol Aging 25:675–683

    Article  PubMed  CAS  Google Scholar 

  7. Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease. Neurobiol Aging 25:663–674

    Article  PubMed  CAS  Google Scholar 

  8. Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T (2009) Inflammation in Alzheimer's disease: amyloid-β oligomers trigger innate immunity defence via pattern recognition receptors. Progr Neurobiol 87:181–194

    Article  CAS  Google Scholar 

  9. Watters JJ, Schartner JM, Badie B (2005) Microglia function in brain tumors. J Neurosci Res 81:447–455

    Article  PubMed  CAS  Google Scholar 

  10. Weinbaum S, Tarbell JM, Damiano ER (2007) The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9:121–167

    Article  PubMed  CAS  Google Scholar 

  11. Ariga T, McDonald MP, Yu RK (2008) Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review. J Lipid Res 49:1157–1175

    Article  PubMed  CAS  Google Scholar 

  12. Yanagisawa K (2007) Role of gangliosides in Alzheimer's disease. Biochim Biophys Acta 1768:1943–1951

    Article  PubMed  CAS  Google Scholar 

  13. Chava AK, Bandyopadhyay S, Chatterjee M, Mandal C (2004) Sialoglycans in protozoal diseases: their detection, modes of acquisition and emerging biological roles. Glycoconj J 20:199–206

    Article  PubMed  CAS  Google Scholar 

  14. Martin-Rehrmann MD, Hoe HS, Capuani EM, Rebeck GW (2005) Association of apolipoprotein J-positive β-amyloid plaques with dystrophic neurites in Alzheimer's disease brain. Neurotox Res 7:231–242

    Article  PubMed  CAS  Google Scholar 

  15. Kida E, Choi-Miura NH, Wisniewski KE (1995) Deposition of apolipoproteins E and J in senile plaques is topographically determined in both Alzheimer's disease and Down's syndrome brain. Brain Res 685:211–216

    Article  PubMed  CAS  Google Scholar 

  16. McGeer PL, Klegeris A, Walker DG, Yasuhara O, McGeer EG (1994) Pathological proteins in senile plaques. Tohoku J Exp Med 174:269–277

    Article  PubMed  CAS  Google Scholar 

  17. Wilson MR, Yerbury JJ, Poon S (2008) Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity. Mol Biosyst 4:42–52

    Article  PubMed  CAS  Google Scholar 

  18. Kalaria RN, Galloway PG, Perry G (1991) Widespread serum amyloid P immunoreactivity in cortical amyloid deposits and the neurofibrillary pathology of Alzheimer's disease and other degenerative disorders. Neuropathol Appl Neurobiol 17:189–201

    Article  PubMed  CAS  Google Scholar 

  19. Iwamoto N, Nishiyama E, Ohwada J, Arai H (1994) Demonstration of CRP immunoreactivity in brains of Alzheimer's disease: immunohistochemical study using formic acid pretreatment of tissue sections. Neurosci Lett 177:23–26

    Article  PubMed  CAS  Google Scholar 

  20. Crocker PR, Paulson JC, Varki A (2007) Siglecs and their roles in the immune system. Nat Rev Immunol 7:255–266

    Article  PubMed  CAS  Google Scholar 

  21. Von Gunten S, Bochner BS (2008) Basic and clinical immunology of Siglecs. Ann NY Acad Sci 1143:61–82

    Google Scholar 

  22. Varki A (2008) Sialic acids in human health and disease. Trends Mol Med 14:351–360

    Article  PubMed  CAS  Google Scholar 

  23. Crocker PR, Redelinghuys P (2008) Siglecs as positive and negative regulators of immune system. Biochem Soc Trans 36:1467–1471

    Article  PubMed  CAS  Google Scholar 

  24. Quarles RH (2007) Myelin-associated glycoprotein (MAG): past, present and beyond. J Neurochem 100:1431–1448

    PubMed  CAS  Google Scholar 

  25. McMillan SJ, Crocker PR (2008) CD33-related sialic-acid-binding immunoglobulin-like lectins in health and disease. Carbohydr Res 343:2050–2056

    Article  PubMed  CAS  Google Scholar 

  26. Chong ZZ, Maise K (2007) The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury. Histol Histopathol 22:1251–1267

    PubMed  CAS  Google Scholar 

  27. Rapoport E, Mikhalyov I, Zhang J, Crocker P, Bovin N (2003) Ganglioside binding pattern of CD33-related Siglecs. Bioorg Med Chem Lett 13:675–678

    Article  PubMed  CAS  Google Scholar 

  28. Angata T, Kerr C, Greaves DR, Varki NM, Crocker PR, Varki A (2002) Cloning and characterization of human Siglec-11. A recently evolved signaling molecule that can interact with SHP-1 and SHP-2 and is expressed by tissue macrophages, including brain microglia. J Biol Chem 277:24466–24474

    Article  PubMed  CAS  Google Scholar 

  29. Hayakawa T, Angata T, Lewis AL, Mikkelsen TS, Varki NM, Varki A (2005) A human-specific gene in microglia. Science 309:1693

    PubMed  CAS  Google Scholar 

  30. Wang B, Miller JB, McNeil Y, McVeagh P (1998) Sialic acid concentration of brain gangliosides: variation amongst eight mammalian species. Comp Biochem Physiol 119A:435–439

    CAS  Google Scholar 

  31. Kim YJ, Kim KS, Do S, Kim CH, Kim SK, Lee YC (1997) Molecular cloning and expression of human α2, 8-sialyltransferase (hST8Sia V). Biochem Biophys Res Commun 235:327–330

    Article  PubMed  CAS  Google Scholar 

  32. Bernardo A, Harrison FE, McCord M, Zhao J, Bruchey A, Davies SS, Jackson Roberts L 2nd, Mathews PM, Matsuoka Y, Ariga T, Yu RK, Thompson R, McDonald MP (2009) Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice. Neurobiol Aging (in press)

  33. Iwamoto N, Suzuki Y, Makino Y, Haga C, Kosaka K, Iizuka R (1990) Cell membrane changes in brains manifesting senile plaques: an immunohistochemical study of GM1 membranous ganglioside. Brain Res 522:152–156

    Article  PubMed  CAS  Google Scholar 

  34. Nishinaka T, Iwata D, Shimada S, Kosaka K, Suzuki Y (1993) Anti-ganglioside GD1a monoclonal antibody recognizes senile plaques in the brains of patients with Alzheimer-type dementia. Neurosci Res 17:171–176

    Article  PubMed  CAS  Google Scholar 

  35. Mukhin DN, Chao FF, Kruth HS (1995) Glycosphingolipid accumulation in the aortic wall is another feature of human atherosclerosis. Arterioscler Thromb Vasc Biol 15:1607–1615

    PubMed  CAS  Google Scholar 

  36. Nobile-Orazio E, Carpo M, Scarlato G (1994) Gangliosides. Their role in clinical neurology. Drugs 47:576–585

    Article  PubMed  CAS  Google Scholar 

  37. Svennerholm L (1994) Gangliosides—a new therapeutic agent against stroke and Alzheimer's disease. Life Sci 55:2125–2134

    Article  PubMed  CAS  Google Scholar 

  38. Yerbury JJ, Poon S, Meehan S, Thompson B, Kumita JR, Dobson CM, Wilson MR (2007) The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with prefibrillar structures. FASEB J 21:2312–2322

    Article  PubMed  CAS  Google Scholar 

  39. Chiang KC, Goto S, Chen CL, Lin CL, Lin YC, Pan TL, Lord R, Lai CY, Tseng HP, Hsu LW, Lee TH, Yokoyama H, Kunimatsu M, Chiang YC, Hashimoto T (2000) Clusterin may be involved in rat liver allograft tolerance. Transpl Immunol 8:95–99

    Article  PubMed  CAS  Google Scholar 

  40. Nitsch RM, Hock C (2008) Targeting β-amyloid pathology in Alzheimer's disease with Aβ immunotherapy. Neurotherapeutics 5:415–420

    Article  PubMed  CAS  Google Scholar 

  41. Mohajeri MH (2007) The underestimated potential of the immune system in prevention of Alzheimer's disease pathology. Bioessays 29:927–932

    Article  PubMed  CAS  Google Scholar 

  42. Rabano A, Jimenez-Huete A, Acavedo B, Calero M, Ghiso J, Valdes I, Gavilondo J, Frangione B, Mendez E (2005) Diversity of senile plaques in Alzheimer's disease as revealed by a new monoclonal antibody that recognizes an internal sequence of the Aβ peptide. Curr Alzheimer Res 2:409–417

    Article  PubMed  CAS  Google Scholar 

  43. Morgan D (2009) The role of microglia in antibody-mediated clearance of amyloid-β from the brain. CNS Neurol Disord Drug Targets 8:7–15

    Article  PubMed  CAS  Google Scholar 

  44. Comelli EM, Head SR, Gilmartin T, Whisenant T, Haslam S, North SJ, Wong NK, Kudo T, Narimetsu H, Esko JD, Drickamer K, Dell A, Paulson JC (2006) A focused microarray approach to functional glycomics: transcriptional regulation of the glycome. Glycobiology 16:117–131

    Article  PubMed  CAS  Google Scholar 

  45. Malm TM, Koistinaho M, Parepalo M, Vatanen T, Ooka A, Karlsson S, Koistinaho J (2005) Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to β-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis 18:134–142

    Article  PubMed  CAS  Google Scholar 

  46. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49:489–502

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was financially supported by grants from the Academy of Finland, The Finnish Eye Foundation, and the University of Kuopio, Finland. The authors thank Dr. Ewen MacDonald for checking the language of the manuscript.

Author information

Authors and Affiliations

  1. Department of Neurology, Institute of Clinical Medicine, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland

    Antero Salminen

  2. Department of Neurology, University Hospital of Kuopio, P.O. Box 1777, 70211, Kuopio, Finland

    Antero Salminen

  3. Department of Ophthalmology, Institute of Clinical Medicine, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland

    Kai Kaarniranta

  4. Department of Ophthalmology, University Hospital of Kuopio, P.O. Box 1777, 70211, Kuopio, Finland

    Kai Kaarniranta

Authors
  1. Antero Salminen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai Kaarniranta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antero Salminen.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Salminen, A., Kaarniranta, K. Siglec receptors and hiding plaques in Alzheimer's disease. J Mol Med 87, 697–701 (2009). https://doi.org/10.1007/s00109-009-0472-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-009-0472-1

Keywords

search

Navigation