Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

The ultrastructural localization of sulfated proteoglycans is identical in the amyloids of Alzheimer's disease and AA, AL, senile cardiac and medullary carcinoma-associated amyloidosis


The cationic dyes cuprolinic blue and ruthenium red were used to ultrastructurally localize proteoglycans (PGs) within the neuritic plaque and neurofibrillary tangle of Alzheimer's disease. Highly sulfated PGs were specifically localized to the amyloid fibril of the neuritic plaque and the paired filaments of the neurofibrillary tangle. This demonstrates that highly sulfated PGs either comprise part of the Alzheimer's amyloid fibril and paired filament or are intimately associated with them. Four unrelated types of amyloid — AA (inflammation-associated), AL (immunoglobulin light chain), senile cardiac (prealbumin) and medullary carcinoma-associated amyloid (procalcitonin) — showed an identical pattern of localization of highly sulfated PG to the different amyloid fibrils. This constant close spatial relationship between PGs and diverse amyloid proteins suggests that PGs may play a role in amyloidogenesis.

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


  1. 1.

    Alvarado MV, Castejon HV (1984) Histochemical demonstration of cytoplasmic glycosaminoglycans in the macroneurons of the human central nervous system. J Neurosci Res 11:13–26

  2. 2.

    Anderson MJ, Fambrough DM (1983) Aggregates of acetylcholine receptors are associated with plaques of a basal lamina heparan sulfate proteoglycan on the surface of skeletal muscle fibers. J Cell Biol 97:1396–1411

  3. 3.

    Blessed G, Tomlinson BE, Roth M (1968) The association between quantiative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry 114:797–811

  4. 4.

    Bowen DM, Benton JS, Spillane JA, Smith CCT, Allen SJ (1982) Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. J Neurol Sci 57:191–202

  5. 5.

    Branford White GJ, Tones T (1978) Glycosaminoglycans in synaptosomes. Biochem Soc Trans 6:646–647

  6. 6.

    Brun A, Gustafson L (1976) Distribution of cerebral degenerationin Alzheimer's disease. A clinical pathological study. Arch Psychiatr Nervenkr 223:15–25

  7. 7.

    Buckley KM, Schweitzer ES, Mijanich GP, Glift-Ogrady L, Kushner PD, Reichardt LF, Kelly RB (1983) A synaptic vesicle antigen is restricted to the junctional region of the presynaptic plasma membrane. Proc Natl Acad Sci USA 80:7342–7346

  8. 8.

    Castano EM, Frangione B (1988) Human amyloidosis, Alzheimer's disease and related disorders. Lab Invest 58:122–132

  9. 9.

    Cole GJ, Loewy A, Glaser L (1986) Neuronal cell-cell adhesion depends on interactions of N-CAM with heparinlike molecules. Nature 320:445–447

  10. 10.

    Dekosky ST, Bass NH (1982) Aging, senile dementia and the intralaminar microchemistry of cerebral cortex. Neurology 32:1227–1233

  11. 11.

    Eaves ED, Glenner GG (1968) X-ray diffraction studies on amyloid filaments. J Histochem Cytochem 16:673–677

  12. 12.

    Edgar D, Timpl R, Thoenen H (1984) The heparin-binding domain of laminin is responsible for its effects on neurite outgrowth and neuronal survival. EMBO J 3:1463–1468

  13. 13.

    Glenner GG (1983) Alzheimer's disease: miltiple cerebral amyloidosis. Banbury Rep 15:137–144

  14. 14.

    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 120:885–898

  15. 15.

    Goldgaber D, Lerman MI, McBride OW, Saffiotti V, Gafdusek DC (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science 235:877–880

  16. 16.

    Gotlieb L, Bav Sella P, Jaichenko J, Shustack A (1987) Ruthenium red-stained polyanionic fixed charges in peritoneal microvessels. Nephron 47:22–28

  17. 17.

    Ihara Y (1986) Phosphorylated tau: a major antigenic determinant of paired belical filaments in Alzheimer's disease. In: Kitani K (ed) Liver and aging. Elsevier, New York, pp 223–231

  18. 18.

    Kang J, Lemaire H, Untabeck A, Salbaum JM, Masters CL, Grzeschik K, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736

  19. 19.

    Kanwar YS, Farquhar MG (1979) Isolation of glycosaminoglycans (heparan sulfate) from glomerular basement membranes. Proc Natl Acad Sci USA 76:4493–4497

  20. 20.

    Katzman R (1986) Alzheimer's disease. N Engl J Med 314:964–973

  21. 21.

    Kelly RB (1985) Exocytotic release from nerve terminals. Arch Neurol 42:1120 [abstr]

  22. 22.

    Kelly RB, Buckley KM, Burgess FL, Carlson SS, Carni P, Hooper JE, Katzen A, Moore HP, Pfeffer SR, Schroer TA (1983) Membrane traffic in neurons and peptide secreting cells. Cold Spring Harbor Symp Quant Biol 48:697–705

  23. 23.

    Kirschner DA, Abraham C, Selkoe DJ (1986) X-ray diffraction from intra-neuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer's disease indicates cross-beta conformation. Proc Natl Acad Sci USA 83:503–507

  24. 24.

    Margolis RU, Margolis RK, Chang LB, Preti C (1975) Glycosaminoglycans of brain during development. Biochemistry 14:85–88

  25. 25.

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

  26. 26.

    Mathew WD, Greenspan RJ, Lander AD (1985) Immunopurification and characterization of a neuronal heparan sulfate proteoglycan. Neuroscience 5:1842

  27. 27.

    McCubbin WD, Kay CM, Narindrasorasak S, Kisilevsky R (1989) Cireular dischroism and fluorescence studies on two murine serum amyloid A proteins. Biochem J (in press)

  28. 28.

    McGeer PL, McGeer EC, Suzuki J, Dolman CF, Nagai T (1984) Aging, Alzheimer's disease and the cholinergic system of the basal forebrain. Neurology 34:741–745

  29. 29.

    Merz PA, Wisniwski HM, Somerville SA, Bobin SA, Masters CL, Iqbal K (1983) Ultrastructural morphology of amyloid fibrils from neuritic and amyloid plaques. Acta Neuropathol (Berl) 60:113–124

  30. 30.

    Miyakawa T, Shimoji A, Kwamoto R, Higuchi Y (1982) The relationship between senile plaques and cerebral blood vessels in Alzheimer's disease and senile dementia. Virchows Arch [B] 40:121–129

  31. 31.

    Myers DB, Highton TC, Ryans DB (1969) Acid mucopolysaccharides closely associated with collagen fibrils in normal human synovium. Ultrastr Res 28:203–213

  32. 32.

    Norling B, Westermark GT, Westermark P (1988) Immunohistochemical identification of heparan sulphate proteoglycan in secondary systemic amyloidosis. Clin Exp Immunol 73:333–337

  33. 33.

    O'Leary TJ, Levin IW (1985) Secondary structure of endocrine amyloid: improved spectroscopy of medullary carcinoma of the thyroid. Lab Invest 53:240–242

  34. 34.

    Perry EK, Tomlinson BE, Blessed G, Bergman K, Gibson PH, Perry RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 2:1457–1459

  35. 35.

    Perry G, Mulvihill P, Manetto V, Antilio-Gambetti L, Gambetti P (1987) Immunocytochemical properties of Alzheimer straight filaments. J Neurosci 7:3736–3738

  36. 36.

    Pycock C, Blachko E, Bergquist U, Uvnas B (1975) On the possible involvement of sulphomucopolysacchrides in the storage of catecholamines within the central nervous system. Acta Physiol Scand 95:373–382

  37. 37.

    Schubert D, LaCorbiere M, Klier FG, Birdwell C (1983) A role for adherons in neural retinal cell adhesion. J Cell Biol 96:990–999

  38. 38.

    Schubert D, LaCorbiere M, Klier FG, Birdwell G (1983) The structure and function of myoblast adheron. Cold Spring Harbor Symp Quant Biol 48:539–549

  39. 39.

    Schubert D, Schroder R, LaCorbiere M, Saitoh T, Cole G (1988) Amyloid B Protein precursor is possibly a heparan sulfate proteoglycan core protein. Science 241:223–226

  40. 40.

    Scott JE (1980) Collagen-proteoglycan interactions. Localization of proteoglycans in tendon by electron microscopy. Biochem J 187:887–891

  41. 41.

    Scott JE, Dorling J (1965) Differential staining of acid glycosaminoglycans (mucopolysaccharides) by Alcian blue in salt solutions. Histochemie 5:221–223

  42. 42.

    Selkoe DJ (1986) Altered structural proteins in plaques and tangles: what do they tell us about the biology of Alzheimer's disease? Neurobiol Aging 7:425–432

  43. 43.

    Selkoe DJ, Ihara Y, Abraham C, Rasool CG, McCloskey AA (1983) Biochemical and unmunocytochemical studies of Alzheimer paired helical filamenis. In: Katzman R (ed) Biological aspects of Alzheimer's disease. Banbury Rep 15. Cold Spring Harbor, New York

  44. 44.

    St. George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Frommelt P, Amaduni L, Sorbi S, Piacentini S, Stewart GD, Hobbs WJ, Conneally PM, Gusella JF (1987) The genetic defect causing familial Alzheimer disease maps on chromosome 21. Science 235:885–890

  45. 45.

    Snow AD, Kisilevsky R (1987) A close ultrastraciural relationship between sulfated proteoglycans and AA amyloid fibrils. Lab Invest 57:687–698

  46. 46.

    Snow AD, Willmer J, Kisilevsky R (1976) Sulfated glycosaminoglycans in Alzheimer's disease. Hum Pathol 18:506–510

  47. 47.

    Snow AD, Willmen J, Kisilevksy R (1987) Sulfated glycosaminoglycans: a common constituent of all amyloids? Lab Invest 56:120–123

  48. 48.

    Snow AD, Kisilevsky R, Wight TN (1989) Immunolocalization of heparan sulfate proteoglycans to AA amyloid deposition sites in spleen during experimental amyloidosis. In: Isobe I (ed) Proc Vth Int Symp Amyloidosis. Plenum Press, New York (in press)

  49. 49.

    Snow AD, Lara S, Nochlin D, Wight TN (1989) Cationic dyes reveal proteoglycans structurally integrated within the characteristic lesions of Alzheimer's disease. Acta Neuropathol 78:113–123

  50. 50.

    Tanzi RE, St. George Hyslop PH, Haines JL, Polinsky R, Nee L, Foncin JF, Neve RL, McClatchey AI, Conneally PM, Gusella JF (1987) The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloidβ-protein gene. Nature 329:156–157

  51. 51.

    Terry RD (1963) The fine structure of neurofibrillary tangles in Alzheimer's disease. J Neuropathol Exp Neurol 22:629–642

  52. 52.

    Terry RD, Gonatas NK, Weiss M (1964) Ultrastructural studies in Alzheimer's presenile dementia. Am J Pathol 44:269–297

  53. 53.

    Turnell WG, Sarra R, Glover IDC (1986) Analysis of X-ray scattering from human AA fibrils using secondary structure predictions of human SAA. In: Glenner GG, Osserman EF, Benditt EP, Calkins E, Cohen AS, Zucker-Franklin D (eds) Proceedings of the IVth International Symposium of Amyloidosis. Plenum Press, New York, pp 40–46

  54. 54.

    Vaccaro CA, Brody JS (1979) Ultrastructural localization and characterization of proteoglycans in the pulmonary alveolus. Am Rev Respir Dis 120:901–910

  55. 55.

    Van Broeckhoven C, Genthe AM, Vanderberghe A, Horsthemke B, Backhovens H, Raeymackers P, Van Hul W, Wehnert A, Gherens J, Cras P, Bruyland M, Martin JJ, Salbaum M, Multhamp G, Masters CL, Beyreuther F, Gurling HMD, Mullan JM, Holland A, Barton A, Irving N, Williamson R, Richards SJ, Hardy JA (1987) Failure of familial Alzheimer's disease to segregate with the A4 amyloid gene in several European families. Nature 329: 153–155

  56. 56.

    Van Kuppevelt THMSM, Domen JG, Cremers FPM, And Kyper CMA (1984) Staining of proteoglycans in mouse lung alveoli. I. Ultrastructural localization of anionic sites. Histochem J 16:657–669

  57. 57.

    Van Kuppevelt THMSM, Janssen HMS, van Beuningen HM, Cheung K, Schijen MMA, Kuyper CMA, Veerkamp JH (1987) Isolation and characterization of a collagen fibrilassociated dermatan sulphate proteoglycan from bovine lung. Biochim Biophys Acta 926:296–309

  58. 58.

    Vigny M, Martin GR, Grotendorst GR (1983) Interactions of assymetric forms of acetylcholinesterase with basement membrane components. J Biol Chem 258:8794–8798

  59. 59.

    Willmer J, Snow AD, Kisilevsky R (1986) The demonstration of sulphated glycosaminoglycans in association with the amyloidotic lesions of Alzheimer's disease. J Neuropathol Exp Neurol 45:340 [abstr]

  60. 60.

    Wisniewski HM, Terry RD (1973) Re-examination of the pathogenesis of the senile plaque. In: Zimmerman HM (ed) Progress in neuropathology. Grune and Stratton, New York, pp 1–26

  61. 61.

    Wisnkewski HM, Navang HK, Terry RD (1976) Neurofibrillary tangles of paired helical filaments. J Neurol Sci 27:173–181

  62. 62.

    Wisniewski KE, Dalton AJ, Crapper-McLachlan DR, Wen GY, Wisniewski HM (1985) Alzheimer's disease in Down's syndrome: clinicopathological studies. Neurology 35: 957–961

Download references

Author information

Correspondence to I. D. Young.

Additional information

Supported by Grant MT 3153 from the Medical Research Council of Canada and by a Dean's MRC award from Queen's University

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Young, I.D., Willmer, J.P. & Kisilevsky, R. The ultrastructural localization of sulfated proteoglycans is identical in the amyloids of Alzheimer's disease and AA, AL, senile cardiac and medullary carcinoma-associated amyloidosis. Acta Neuropathol 78, 202–209 (1989).

Download citation

Key words

  • Alzheimer's disease
  • Amyloid
  • Neuritic plaque
  • Neurofibrillary tangle
  • Proteoglycans