Neurotoxicity Research

, Volume 12, Issue 4, pp 269–274

The role of novel chitin-like polysaccharides in Alzheimer disease

  • Rudy J. Castellani
  • George Perry
  • Mark A. Smith


While controversy over the role of carbohydrates in amyloidosis has existed since the initial recognition of amyloid, current understanding of the role of polysaccharides in the pathogenesis of amyloid deposition of Alzheimer disease and other amyloidoses is limited to studies of glycoconjugates such as heparan sulfate proteglycan. We hypothesized that polysaccharides may play a broader role in light of 1) the impaired glucose utilization in Alzheimer disease; 2) the demonstration of amylose in the Alzheimer disease brain; 3) the role of amyloid in Alzheimer disease pathogenesis. Specifically, as with glucose polymers (amyloid), we wanted to explore whether glucosamine polymers such as chitin were being synthesized and deposited as a result of impaired glucose utilization and aberrant hexosamine pathway activation. To this end, using calcofluor histochemistry, we recently demonstrated that amyloid plaques and blood vessels affected by amyloid angiopathy in subjects with sporadic and familial Alzheimer disease elicit chitin-type characteristics. Since chitin is a highly insoluble molecule and a substrate for glycan-protein interactions, chitin-like polysaccharides within the Alzheimer disease brain could provide a scaffolding for amyloid-\ deposition. As such, glucosamine may facilitate the process of amyloidosis, and/or provide neuroprotection in the Alzheimer disease brain.


Alzheimer disease Chitin Amyloid-\ Plaques Amyloidoses Glucosamine Calcofluor 


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  1. Bakkers J, CE Semino, H Stroband, JW Kijne, PW Robbins and HP Spaink (1997) An important developmental role for oligosaccharides during early embryogenesis of cyprinid fish.Proc. Natl. Acad. Sci. USA 94, 7982–7986.PubMedCrossRefGoogle Scholar
  2. Bame KJ, J Danda, A Hassall and S Tumova (1997) Aβ(1–40) prevents heparinase-catalyzed degradation of heparin sulfate glycosaminoglycans and proteoglycansin vitro.J. Biol. Chem. 272, 17005–17011.PubMedCrossRefGoogle Scholar
  3. Berenson GS, ER Dalferes, H Ruitz and B Radhakrishmamurthy (1969) Changes of acid mucopolysaccharides in the heart involved by amyloidosis.Am. J. Cardiol. 24, 358–364.PubMedCrossRefGoogle Scholar
  4. Bitter T and H Muir (1965) Mucopolysaccharides in amyloidosis.Lancet 1, 819.PubMedCrossRefGoogle Scholar
  5. Brownlee M (2000) Biochemistry and molecular cell biology of diabetic complications.Nature 414, 813–820.CrossRefGoogle Scholar
  6. Castellani RJ, AE Fortino, R Common, G Perry, B Ghetti and MA Smith (2004) Calcofluor statins amyloid-beta deposits.J. Neuropathol Exp. Neurol. 63, 524.Google Scholar
  7. Castellani RJ, SL Siedlak, AE Fortino, G Perry, B Ghetti and MA Smith (2005) Chitin-like polysacchandes in Alzheimer’s disease brains.Curr. Alzheimer Res. 2, 419–423PubMedCrossRefGoogle Scholar
  8. Castillo GM, W Lukito, TN Wight and AD Snow (1999) The sulfate moieties of glycosaminoglycans are critical for the enhancement of β-amyloid protein fibril formation.J. Neurochem. 72, 1681–1687.PubMedCrossRefGoogle Scholar
  9. Clausen J and HE Christensen (1964) Paraproteins and acid mucopolysaccharides in primary amyloidosis.Acta Pathol Microbiol. Scand. 60, 493–510.PubMedGoogle Scholar
  10. Cotran RS, V Kumar, T Collins and SL Robbins (Eds.) (1999)Robbins Pathologic Basis of Disease, 6th Edition (WB Saunders, Philadelphia, PA, USA), pp 1425.Google Scholar
  11. Dalferes ER, B Radhakrislunamurthy and GS Berenson (1967) Acid mucopolysaccharides in amyloid tissues.Acta Biochem. Biophys. 118, 284–291.CrossRefGoogle Scholar
  12. DeWitt DA, J Silver, DR Canning and G Perry (1993) Chondroitin sulfate proteoglycans are associated with the lesions of Alzheimer’s disease.Exp. Neurol. 121, 149–152.PubMedCrossRefGoogle Scholar
  13. Fraser PE, JT Nguyen, DT Chin and DA Kirschner (1992) Effects of sulfate ions on Alzheimer beta/A4 peptide assemblies: implications for amyloid fibril-proteoglycan interactions.J. Neurochem. 59, 1531–1540.PubMedCrossRefGoogle Scholar
  14. Friedreich N and A Kekule (1859) Zur amyloidfrage.Virch Arch. Path. Anat. Physiol. 16, 50–65.CrossRefGoogle Scholar
  15. Garcia-Zapien AG, A Gonzales-Robles and J Mora-Galindo (1999) Congo red effect on cyst viability and cell wall structure of encysting.Entamoeba invadens. Arch. Med. Res. 30, 106–115.CrossRefGoogle Scholar
  16. Glaser L and DH Brown (1957) The synthesis of chitin in cellfiee extracts of Neurospora Crassa.J. Biol. Chem. 228, 729–742.PubMedGoogle Scholar
  17. Houston DR, AD Recklies, JC Krupa and DMF van Aalten (2003) Structure and ligand-induced conformational change of the 39-kDa glycoprotein from human articular chondrocytes.J Biol. Chem. 278, 30206–30212.PubMedCrossRefGoogle Scholar
  18. Huang L, RI Hollingsworth, R Castellani and B Zipser (2004) Accumulation of high-molecular-weight amylose in Alzheimer’s disease brains.Glycobiology 14, 409–416.PubMedCrossRefGoogle Scholar
  19. Ishii K, M Sasaki, H Kitagaki, S Yamaji, S Sakamoto, K Matsuda and E Mori (1997) Reduction of cerebellar glucose metabolism in advanced Alzheimer’s disease.J. Nucl. Med. 38, 925–928.PubMedGoogle Scholar
  20. Joseph J, B Shukitt-Hale, NA Denisova, A Martin, G Perry and MA Smith (2001) Copernicus revisited anyloid beta in Alzheimer’s disease.Neurobiol. Aging. 22, 131–146.PubMedCrossRefGoogle Scholar
  21. Klis FM, P Mol, K Hellingwerf and S Brul (2002) Dynamics of cell wall structure inSaccharomyces cerevisiae.FEMS Microbiol Rev. 26, 239–259.PubMedCrossRefGoogle Scholar
  22. Ling H and AD Recklies (2004) The chitinase 3-like protein HC-gp39 inhibits cellular responses to the inflammatory cytokines interleukin 1 and tumor necrosis factor-α.Biochem. J. 380, 651–659.PubMedCrossRefGoogle Scholar
  23. Meyer MF and G Kreil (1996) Cells expressing the DG42 gene from earlyXenopus embryos synthesize hyaluronan.Proc. Natl. Acad. Sci. USA 93, 4543–4547.PubMedCrossRefGoogle Scholar
  24. Niwa K, K Kazama, SG Younkin, GA Carlson and C Iadecola (2002) Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor proteinNeurobiol. Dis. 9, 61–68.PubMedCrossRefGoogle Scholar
  25. Pennock CA (1968) Association of acid mucopolysaccharides with isolated amyloid fibrils.Nature 21, 753–754CrossRefGoogle Scholar
  26. Pennock CA, J Bruns and G Massarella (1968) Histochemical investigation of acid mucosubstances in secondary amyloidosis.J. Clin. Pathol. 21, 578–581.PubMedCrossRefGoogle Scholar
  27. Recklies AD, C White and H Ling (2002) The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways.Biochem. J. 365, (Pt. 1), 119–126.PubMedCrossRefGoogle Scholar
  28. Rottkamp CA, AK Raina, X Zhu, E Gaier, AI Bush, CS Atwood, M Chevion, G Perry and MA Smith (2001) Redoxactive iron mediates amyloid-beta toxicity.Free Radic. Biol. Med. 30, 447–450.PubMedCrossRefGoogle Scholar
  29. Semino CE, CA Specht, A Raimondi and PW Robbins (1996) Homologs of theXenopus developmental gene DG42 are present in zebrafish and mouse and are involved in the synthesis of Nod-like chitin oligosaccharides during early embryogenesis.Proc. Natl. Acad. Sci. USA 93, 4548–4553.PubMedCrossRefGoogle Scholar
  30. Simpson IA, KR Chundu, T Davies-Hill, WG Honer and P Davies (1994) Decreased concentrations of GLUTI and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease.Ann. Neurol. 35, 546–551.PubMedCrossRefGoogle Scholar
  31. Smith MA, G Casadesus, JA Joseph and G Perry (2002) Amyloid-sb and τ serve antioxidant functions in the aging and Alzheimer brain.Free Radic Biol. Med. 33, 1194–1199.PubMedCrossRefGoogle Scholar
  32. Snow AD and R Kisilevsky (1985) Temporal relationship between glycosaminoglycan accumulation and amyloid deposition during experimental amyloidosis A histochemical study.Lab. Invest. 53, 37–44.PubMedGoogle Scholar
  33. Snow AD, J Willmer and R Kisilevsky (1987) A close ultrastructural relationship between sulfated proteoglycans and AA amyloid fibrils.Lab. Invest. 57, 687–698.PubMedGoogle Scholar
  34. Snow AD, H Mar, D Nochlin, K Kimata, M Sate, S Suzuki, J Hassell and TN Wight (1988) The presence of hepaian sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer’s disease.Am. J. Pathol. 133, 456–463.PubMedGoogle Scholar
  35. Snow AD, R Sekiguchi, D Nochlin, P Fraser, K Kimata, A Mizutani, M Arai, WA Schreier and DG Morgan (1994) An important role of heparan sulfate proteoglycan (Perlecan in a model system for the deposition and persistence of fibrillan Abeta-unyloid in rat brain.Neuron 12, 219–234.PubMedCrossRefGoogle Scholar
  36. Szumanska G, AW Vorbrodt, TI Mandybur and HM Wisniewski (1987) Lectin histochemistry of plaques and tangles in Alzheimer’s disease.Acta Neuropathol. 73, 1–11.PubMedCrossRefGoogle Scholar
  37. Tanwar MK, MR Gilbert and EC Holland (2002) Gene expression microarray analysis reveals YKL-40 to be a potential serum marker for malignant character in human glioma.Cancer Res 62, 4361–4368.Google Scholar
  38. Ueno H, F Nakamura, M Murakami, M Okunura, T Kadosawa and T Fujinag (2001) Evaluation effects of chitosan for the extracellular matrix production by fibroblasts and the growth factors production by macrophagesBiomaterials 22, 2125–2130PubMedCrossRefGoogle Scholar
  39. Verkkoniemi A, H Kalimo, A Paetau, M Somer, T Iwatsubo, J Hardy and M Haltia (2001) Variant Alzheimer disease with spastic parapariesis neuropathological phenotype.J. Neuropathol. Exp. Neurol. 60, 483–492.PubMedGoogle Scholar
  40. Virchow R (1854) On a new substance found in the human brain and spinal cord which reacts chemically like celluloseVirch. Arch. Path. Anat. Physiol. 6, 135–137CrossRefGoogle Scholar
  41. Wyss-Coray T and L Mucke (2002) Inflammation in neurodegenerative disease — a double-edged sword.Neuron 35, 419–432.PubMedCrossRefGoogle Scholar
  42. Yoshida M, N Itano, Y Yamada and K Kimata (2002)In vitro synthesis of hyaluronan by a single protein derived from mouse HAS1 gene and characterization of amano acid residues essential for the activity.J. Biol. Chem. 275, 497–506.CrossRefGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Rudy J. Castellani
    • 1
  • George Perry
    • 2
    • 3
  • Mark A. Smith
    • 2
  1. 1.Department of PathologyUniversity of MarylandBaltimoreUSA
  2. 2.Department of PathologyCase Western Reserve UniversityClevelandUSA
  3. 3.College of SciencesUniversity of Texas at San AntonioSan AntonioUSA

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