HOME > Members > GCOE Organizing Members > Katsuhiko Yanagisawa

Katsuhiko YanagisawaVice-Director, National Institute for Longevity Sciences
National Center for Geriactrics and Gerontology

Specialized field

Molecular neuropathology

Career Summary

1980   Graduated from Niigata University School of Medicine
1984   Visiting Fellow, NINCDS, NIH
1990   Assistant Professor, Department of Neurology, Brain Research Institute, Niigata University
1992   Assistant Professor, Department of Neurology, Tokyo Medicaland Dental University
1994   Assistant Professor, Department of Neuropathology, University of Tokyo
1995   Head, Department of Dementia Research, National Institute for Longevity Sciences
2005-present   Vice-Director, National Institute for Longevity Sciences, National Center for Geriactrics and Gerontology

Research Theme

Molecular mechanism underlying Aß assembly in Alzheimer brain

Research Summary

Molecular mechanism underlying Aß assembly in Alzheimer brain

Purpose: One of the fundamental questions regarding the pathogenesis of Alzheimer disease (AD) is how soluble amyloid ß-protein (Aß) starts to assemble into amyloid fibrils in the brain. We previously identified a novel Aß species in a brain that exhibited early pathological changes of AD such as formation of diffuse plaques. Characterization of the novel Aß species, we concluded that it was a GM1-ganglioside-bound form of Aß (GAß) and that Aß adopts an altered conformation through binding to GM1 ganglioside, which is distinct from those of soluble Aß or Aß in amyloid fibrils. Furthermore, results of our previous studies strongly suggest that GAß acts as an endogenous seed to induce amyloid fibril formation in AD brain (Yanagisawa et al., Nat Med, 1995). The purpose of the present study is twofold; first, to clarify the GAß generation pathway in the brain, and second, to extend the GAß hypothesis into development of therapeutic strategy by seeking drug-like compounds acting as anti-GAß molecules, named as anti-seed internal medicine (ASIM). For this annual report, the progress in the second issue is presented.

Results: To discover small anti-GAß chemical compounds, which potently suppress the amyloid fibril formation in the presence of GM1 ganglioside, we first employed structure-based drug design technique. We investigated the unique molecular structure of the GAß, which is crucial for the emergence of its seed activity. On the basis of the findings obtained from the previous studies of our and other groups (Yanagisawa et al., Nat Med, 1995; Kakio et al., J Biol Chem, 2001; Fezoui and Teplow, J Biol Chem 2002; Yamamoto et al., J Neurochem, 2005; Yamamoto et al., Neuroreport, 2006; Utsumi et al., Glycoconjugate J, 2010), we have determined the segment in the GAß molecule as a target of ASIM, and then, we have inferred its secondary structure theoretically. We have defined the structure of the segment through molecular dynamics analysis of the interaction between Aß molecule and the sugar chain of GM1 ganglioside. Next, based on a target-based strategy, we have performed in silico screening of chemical compounds from chemical libraries containing 450 million drug-like molecules. The 400 chemical compounds were selected by the in silico screening, which are named as virtual hits, and then, were applied to wet screening. Then, to further establish a wet screening system, which is applicable to high throughput screening of compounds from chemical libraries, we attempted to induce GAß-like structure in the absence of lipids such as liposomes, using organic solvents which potently stabilize α-helix structure of proteins. In addition, to characterize raft-like membrane microdomain on neuronal membranes, which is essential GAß generation, we focused on clarification of the pathological significance of familial AD-linked mutations of presenilin. Evidence is now accumulating that presenilin mutations cause AD through loss-of-function but not simply through enhancement of Aß production. Lipid biological study on presenilin mutations may provide a novel insight into pathological mechanism underlying Aß assembly and deposition in brain.

Principal Research Achievement

  1. Keilani S, Lun Y, Stevens AC, Williams HN, Sjoberg ER, Khanna R, Valenzano KJ, Checler F, Buxbaum JD, Yanagisawa K, Lockhart DJ, Wustman BA, Gandy S: Lysosomal Dysfunction in a Mouse Model of Sandhoff Disease Leads to Accumulation of Ganglioside-Bound Amyloid-beta Peptide. J Neurosci, 32, 5223-5236 (2012)
  2. Yagi-Utsumi M, Matsuo K, Yanagisawa K, Gekko K, Kato K: Spectroscopic Characterization of Intermolecular Interaction of Amyloid beta Promoted on GM1 Micelles. Int J Alzheimers Dis, 2011, 925073 (2011)
  3. Yanagisawa K: Newly approved drugs for Alzheimer disease: effectiveness and limitation. Brain Nerve, 63, 863-868 (2011)
  4. Takamura A, Okamoto Y, Kawarabayashi T, Yokoseki T, Shibata M, Mouri A, Nabeshima T, Sun H, Abe K, Urisu T, Yamamoto N, Shoji M, Yanagisawa K, Michikawa M, Matsubara E: Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse. Mol Neurodegener, 6, 20 (2011)
  5. Yanagisawa K: Pathological significance of ganglioside clusters in Alzheimer's disease. J Neurochem, 116, 806-812 (2011)
  6. Yuyama K, Yanagisawa K. Sphingomyelin accumulation provides a favorable milieu for GM1 ganglioside-induced assembly of amyloid beta-protein. Neurosci Lett, 481,168-172 (2010)
  7. Matsuzaki K, Kato K, Yanagisawa K. Aß polymerization through interaction with membrane gangliosides. Biochim Biophys Acta, 1801, 868-877 (2010)
  8. Mao Y, Zhiguo S, Imai Y, Hoshino T, Tero R, Tanaka M, Yamamoto N, Yanagisawa K and Urisu T. Surface-induced phase separation of a sphingomyelin/cholesterol/ganglioside GM1-planar bilayer on mica surfaces and microdomain molecular conformation that accelerates Aß oligomerization. Biochim Biophys Acta, 1798, 1090-1099 (2010)
  9. Oikawa N, Ogino K, Masumoto T, Yamaguchi H, Yanagisawa K. Gender effect on the accumulation of hyperphosphorylated tau in the brains of locus-ceruleus-injured APP transgenic mouse. Neurosci Lett, 468, 243-247 (2010)
  10. Oikawa N, Kimura N, Yanagisawa K. Alzheimer-type tau pathology in advanced nonhuman primate brains harboring substantial amyloid deposition. Brain Res, 1315,137-149 (2010)
  11. Oikawa N, Yamaguchi H, Ogino K, Taki T, Yuyama K, Yamamoto N, Shin RW, Furukawa K, Yanagisawa K. Gangliosides determine the amyloid pathology of Alzheimer disease. Neuroreport, 20, 143-1046 (2009)
  12. Yuyama K, Yanagisawa K. Late endocytic dysfunction as a putative cause of amyloid fibril formation in Alzheimer’s disease. Neuroreport, 109, 1250-1260 (2009)
  13. Yuyama K, Yamamoto N, Yanagisawa K. Accelerated release of exosome-associated GM1 ganglioside (GM1) by endocytic pathway abnormality: another putative pathway for GM1-induced amyloid fibril formation. J Neurochem, 105, 217-224 (2008)
  14. Yamamoto N, Matusbara T, Sato T, Yanagisawa K. Age-dependent high-density clustering of GM1 ganglioside at presynaptic neuritic terminals promotes amyloid ß-protein fibrillogenesis. Biochim Biophys Acta, 1778, 2717-2726 (2008)
  15. Yamamoto N et al. A ganglioside-induced toxix soluble Aß assembly: Its enhanced formation from Aß bearing the Arctic mutation. J. Biol. Chem. 282: 2646-2655 (2007)
  16. Yamamoto N et al. GM1-ganglioside-induced Aß assembly on synaptic membranes of cultured neurons. Biochim. Biophys. Acta. 1768: 1128-1137 (2007)
  17. Yuyama K et al. Chloroquine-induced endocytic pathway abnormalities: cellular model of GM1-ganglioside-induced Aß fibrillogenesis in Alzheimer’s disease. FEBS Lett. 580: 6972-6976 (2006)
  18. Yamamoto N et al. Assembly of hereditary amyloid ß-protein variants in the presence of favorable gangliosides. FEBS Lett. 579: 2185-2190 (2005)
  19. Yamamoto N et al. Suppression of Aß deposition in brain by peripheral administration of Fab fragments of anti-seed antibody. Biochem. Biophys. Res. Commun. 335: 45-47 (2005)
  20. Yamamoto N et al. Cross seeding of wild- and hereditary variant-type amyloid ß-proteins in the presence of gangliosides. J. Neurochem. 95: 1167-1176 (2005)
  21. Yamamoto N et al. Environment- and mutation-dependent aggregation behavior of Alzheimer amyloid ß-protein. J. Neurochem. 90: 62-69 (2004)
  22. Hayashi H et al. A seed for Alzheimer amyloid in the brain. J. Neurosci. 24: 4894-4902 (2004)
  23. Yamamoto N et al. Accelerated Aß aggregation in the presence of GM1-ganglioside-accumulated synaptosomes of aged apoE4-knock-in mouse brain. FEBS Lett. 569: 135-139(2004)
  24. Komano H et al. A new functional screening system for the identification of cDNA encoding a regulator of γ-cleavage. J. Biol. Chem. 277: 39627-39633 (2002)
  25. Michikawa M et al. A novel action of Alzheimer’s amyloid ß-protein (Aß): oligomeric Aß promotes lipid efflux. J. Neurosci. 21: 7226-7235 (2001)
  26. Michikawa M et al. Apolipoprotein E exhibits isoform-specific promotion of lipid efflux from cultured astrocytes and neurons via interaction with cell surface heparan sulfate proteoglycans. J. Neurochem. 74: 1008-1016, (2000)
  27. Mizuno T et al. Cholesterol-dependent generation of a seeding amyloid ß-protein in cell culture. J. Biol. Chem. 274:15110-15114 (1999)
  28. Michikawa M and Yanagisawa K. Inhibition of cholesterol production, and not of nonsterol isoprenoid products induces neuronal cell death. J. Neurochem. 72:2278-2285(1999)
  29. Yanagisawa K et al. GM1 ganglioside-bound amyloid ß-protein (Aß): A possible form of preamyloid in Alzheimer's disease. Nature Med. 1:1062-1066 (1995)
  30. Yanagisawa K et al. A derivative of myelin-associated glycoprotein in cerebrospinal fluid of normal and patients with neurological diseases. Ann. Neurol. 18:464-469 (1985)