Glycoconjugate Journal

, Volume 32, Issue 3–4, pp 87–91 | Cite as

GM1 ganglioside and Alzheimer’s disease

  • Katsuhiko YanagisawaEmail author


Assembly and deposition of amyloid ß-protein (Aß) is an invariable and fundamental event in the pathological process of Alzheimer’s disease (AD). To decipher the AD pathogenesis and also to develop disease-modifying drugs for AD, clarification of the molecular mechanism underlying the Aß assembly into amyloid fibrils in the brain has been a crucial issue. GM1-ganglioside-bound Aß (GAß), with unique molecular characteristics such as having an altered conformation and the capability to accelerate Aß assembly, was discovered in an autopsied brain showing early pathological changes of AD in 1995. On the basis of these findings, it was hypothesized that GAß is an endogenous seed for amyloid fibril formation in the AD brain. A body of evidence that supports this GAß hypothesis has been growing over this past 20 years. In this article, seminal GAß studies that have been carried out to date, including recent ones using unique animal models, are reviewed.


Alzheimer’s disease Amyloid ß-protein Ganglioside GM1-ganglioside-bound Aß (GAß) Seed Conformational transition 



This work was supported by the Research Funding of the Longevity Sciences (25–19) from the National Center for Geriatrics and Gerontology.

Conflict of interest

The author declare that he is free from conflict of interest.


  1. 1.
    Yanagisawa, K., Odaka, A., Suzuki, N., Ihara, Y.: GM1 ganglioside-bound amyloid ß-protein (Aß): a possible form of preamyloid in Alzheimer’s disease. Nat. Med. 1, 1062–1066 (1995)CrossRefPubMedGoogle Scholar
  2. 2.
    Hayashi, H., Kimura, N., Yamaguchi, H., Hasegawa, K., Yokoseki, T., Shibata, M., Yamamoto, N., Michikawa, M., Yoshikawa, Y., Terao, K., Matsuzaki, K., Lemere, C.A., Selkoe, D.J., Naiki, H., Yanagisawa, K.: A seed for Alzheimer amyloid in the brain. J. Neurosci. 24(20), 4894–4902 (2004). doi: 10.1523/JNEUROSCI. 0861-04.2004 CrossRefPubMedGoogle Scholar
  3. 3.
    Yanagisawa, K.: Role of gangliosides in Alzheimer’s disease. Biochim. Biophys. Acta 1768(8), 1943–1951 (2007)CrossRefPubMedGoogle Scholar
  4. 4.
    Ariga, T., McDonald, M.P., Yu, R.K.: Role of ganglioside metabolism in the pathogenesis of Alzheimer’s disease- a review. J. Lipid Res. 49(6), 1157–1175 (2008). doi: 10.1194/jlr. R800007-JLR200 CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Matsuzaki, K., Kato, K., Yanagisawa, K.: Aβ polymerization through interaction with membrane gangliosides. Biochim. Biophys. Acta 1801(8), 868–877 (2010). doi: 10.1016/j.bbalip.2010.01.008 CrossRefPubMedGoogle Scholar
  6. 6.
    Knight, E.M., Williams, H.N., Stevens, A.C., Kim, S.H., Kottwitz, J.C., Morant, A.D., Steele, J.W., Klein, W.L., Yanagisawa, K., Boyd, R.E., Lockhart, D.J., Sjoberg, E.R., Ehrlich, M.E., Wustman, B.A., Gandy, S.: Evidence that small molecule enhancement of β-hexosaminidase activity corrects the behavioral phenotype in Dutch APP(E693Q) mice through reduction of ganglioside-bound Aβ. Mol. Psychiatry (2014). doi: 10.1038/mp.2014.135 Google Scholar
  7. 7.
    Hong, S., Ostaszewski, B.L., Yang, T., O’Malley, T.T., Jin, M., Yanagisawa, K., Li, S., Bartels, T., Selkoe, D.J.: Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82(2), 308–319 (2014). doi: 10.1016/j.neuron.2014.02.027 CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Okabayashi, S., Shimozawa, N., Yasutomi, Y., Yanagisawa, K., Kimura, N.: Diabetes mellitus accelerates Aß pathology in brain accompanied by enhanced GAß generation in non-human primates. PLoS One (2015)Google Scholar
  9. 9.
    McLaurin, J., Franklin, T., Fraser, P.E., Chakrabartty, A.: Structural transitions associated with the interaction of Alzheimer β-amyloid peptides with gangliosides. J. Biol. Chem. 273(8), 4506–4515 (1998)CrossRefPubMedGoogle Scholar
  10. 10.
    Kakio, A., Nishimoto, S., Yanagisawa, K., Kozutsumi, Y., Matsuzaki, K.: Interactions of amyloid β-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry 41(23), 7385–7390 (2002). doi: 10.1074/jbc.M100252200 CrossRefPubMedGoogle Scholar
  11. 11.
    Williamson, M.P., Suzuki, Y., Bourne, N.T., Asakura, T.: Binding of amyloid β-peptide to ganglioside micelles is dependent on histidine-13. Biochem. J. 397(3), 483–490 (2006). doi: 10.1042/BJ20060293 CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Fezoui, Y., Teplow, D.B.: Kinetic studies of amyloid β-protein fibril assembly. Differential effects of alpha-helix stabilization. J. Biol. Chem. 277(40), 36948–36954 (2002). doi: 10.1074/jbc.M204168200 CrossRefPubMedGoogle Scholar
  13. 13.
    Utsumi, M., Yamaguchi, Y., Sasakawa, H., Yamamoto, N., Yanagisawa, K., Kato, K.: Up-and-down topological mode of amyloid β-peptide lying on hydrophilic/hydrophobic interface of ganglioside clusters. Glycoconj. J. 26(8), 999–1006 (2009). doi: 10.1007/s10719-008-9216-7 CrossRefPubMedGoogle Scholar
  14. 14.
    Yagi-Utsumi, M., Kameda, T., Yamaguchi, Y., Kato, K.: NMR characterization of the interactions between lyso-GM1 aqueous micelles and amyloid β. FEBS Lett. 584(4), 831–836 (2010). doi: 10.1016/j.febslet.2010.01.005 CrossRefPubMedGoogle Scholar
  15. 15.
    Ikeda, K., Yamaguchi, T., Fukunaga, S., Hoshino, M., Matsuzaki, K.: Mechanism of amyloid β-protein aggregation mediated by GM1 ganglioside clusters. Biochemistry 50(29), 6433–6440 (2011). doi: 10.1021/bi200771m CrossRefPubMedGoogle Scholar
  16. 16.
    Hoshino, T., Mahmood, M.I., Mori, K., Matsuzaki, K.: Binding and aggregation mechanism of amyloid β-peptides onto the GM1 ganglioside-containing lipid membrane. J. Phys. Chem. B 117(27), 8085–8094 (2013). doi: 10.1021/jp4029062 CrossRefPubMedGoogle Scholar
  17. 17.
    Yagi-Utsumi, M., Matsuo, K., Yanagisawa, K., Gekko, K., Kato, K.: Spectroscopic characterization of intermolecular interaction of amyloid β promoted on GM1 micelles. Int. J. Alzheimers Dis. 2011, 925073 (2010). doi: 10.4061/2011/925073Google Scholar
  18. 18.
    Manna, M., Mukhopadhyay, C.: Binding, conformational transition and dimerization of amyloid-β peptide on GM1-containing ternary membrane: insights from molecular dynamics simulation. PLoS ONE 8(8), e71308 (2013). doi: 10.1371/journal.pone.0071308 CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Kakio, A., Nishimoto, S.I., Yanagisawa, K., Kozutsumi, Y., Matsuzaki, K.: Cholesterol-dependent formation of GM1 ganglioside-bound amyloid β-protein, an endogenous seed for Alzheimer amyloid. J. Biol. Chem. 276(27), 24985–24990 (2001)CrossRefPubMedGoogle Scholar
  20. 20.
    Yuyama, K., Yanagisawa, K.: Sphingomyelin accumulation provides a favorable milieu for GM1 ganglioside-induced assembly of amyloid ß-protein. Neurosci. Lett. 481(3), 168–172 (2010). doi: 10.1016/j.neulet.2010.06.080 CrossRefPubMedGoogle Scholar
  21. 21.
    Mori, K., Mahmood, M.I., Neya, S., Matsuzaki, K., Hoshino, T.: Formation of GM1 ganglioside clusters on the lipid membrane containing sphingomyeline and cholesterol. J. Phys. Chem. B 116(17), 5111–5121 (2012). doi: 10.1021/jp207881k CrossRefPubMedGoogle Scholar
  22. 22.
    Fantini, J., Yahi, N., Garmy, N.: Cholesterol accelerates the binding of Alzheimer’s β-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation. Front. Physiol. 4, 120 (2013). doi: 10.3389/fphys.2013.00120 PubMedCentralPubMedGoogle Scholar
  23. 23.
    Matsubara, T., Iijima, K., Yamamoto, N., Yanagisawa, K., Sato, T.: Density of GM1 in nanoclusters is a critical factor in the formation of a spherical assembly of amyloid β-protein on synaptic plasma membranes. Langmuir 29(7), 2258–2264 (2013). doi: 10.1021/la3038999 CrossRefPubMedGoogle Scholar
  24. 24.
    Oikawa, N., Hatsuta, H., Murayama, S., Suzuki, A., Yanagisawa, K.: Influence of APOE genotype and the presence of Alzheimer’s pathology on synaptic membrane lipids of human brains. J. Neurosci. Res. 92(5), 641–650 (2014). doi: 10.1002/jnr.23341 CrossRefPubMedGoogle Scholar
  25. 25.
    Cataldo, A.M., Peterhoff, C.M., Troncoso, J.C., Gomez-Isla, T., Hyman, B.T., Nixon, R.A.: Endocytic pathway abnormalites precede amyloid ß deposition in sporadic Alzheimer’s disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am. J. Pathol. 157(1), 277–286 (2000)CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Yuyama, K., Yamamoto, N., Yanagisawa, K.: Chloroquine-induced endocytic pathway abnormalities: cellular model of GM1 ganglioside-induced Aß fibrillogenesis in Alzheimer’s disease. FEBS Lett. 580(30), 6972–6976 (2006)CrossRefPubMedGoogle Scholar
  27. 27.
    Yuyama, K., Yanagisawa, K.: Late endocytic dysfuntion as a putative cause of amyloid fibril formation in Alzheimer’s disease. J. Neurochem. 109(5), 1250–1260 (2009). doi: 10.1111/j.1471-4159.2009.06046.x CrossRefPubMedGoogle Scholar
  28. 28.
    Keilani, S., Lun, Y., Stevens, A.C., Williams, H.N., Sjoberg, E.R., Khanna, R., Valenzano, K.J., Checler, F., Buxbaum, J.D., Yanagisawa, K., Lockhart, D.J.: Wustman BA, Gandy S.: Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-β peptide. J. Neurosci. 32(15), 5223–5236 (2012). doi: 10.1523/JNEUROSCI. 4860-11.2012 CrossRefPubMedGoogle Scholar
  29. 29.
    Oikawa, N., Matsubara, T., Fukuda, T., Yasumori, H., Hatsuta H., Murayama, S., Sato, T., Suzuki, A., Yanagisawa, K.: Imbalance in fatty-acid-chain length of gangliosides triggers Alzheimer amyloid deposition. PLoS One (2015)Google Scholar
  30. 30.
    Jarrett, J.T., Lansbury, P.T.: Amyloid fibril formation requires a chemically discriminating nucleation event: studies of an amyloidogenic sequence from the bacterial protein OsmB. Biochemistry 31(49), 12345–12352 (1992)CrossRefPubMedGoogle Scholar
  31. 31.
    Jarrett, J.T., Lansbury, P.T.: Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73(6), 1055–1058 (1993)CrossRefPubMedGoogle Scholar
  32. 32.
    Esler, W.P., Stimson, E.R., Jennings, J.M., Vinters, H.V., Ghilardi, J.R., Lee, J.P., Mantyh, P.W., Maggio, J.E.: Alzheimer’s disease amyloid propagation by a template-dependent dock-lock mechanism. Biochemistry 39(21), 6288–6295 (2000)CrossRefPubMedGoogle Scholar
  33. 33.
    Okada, T., Ikeda, K., Wakabayashi, M., Ogawa, M., Matsuzaki, K.: Formation of toxic Aβ(1–40) fibrils on GM1 ganglioside-containing membranes mimicking lipid rafts: polymorphisms in Aβ(1–40) fibrils. J. Mol. Biol. 382(4), 1066–1074 (2008). doi: 10.1016/j.jmb.2008.07.072 CrossRefPubMedGoogle Scholar
  34. 34.
    Fukunaga, S., Ueno, H., Yamaguchi, T., Yano, Y., Hoshino, M., Matsuzaki, K.: GM1 cluster mediates formation of toxic Aβ fibrils by providing hydrophobic environments. Biochemistry 51(41), 8125–8131 (2012). doi: 10.1021/bi300839u CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Alzheimer’s Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and GerontologyObuJapan

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