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Laboratory for Proteolytic Neuroscience
Takaomi SAIDO
Laboratory Head
Takaomi SAIDO (Ph.D.)
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Research Areas

The aim of our research is to understand the mechanism of brain aging with specific emphasis on the study Alzheimer's disease (AD) through proteolysis. Proteolytic reactions often play critical roles in both physiological and pathological circumstances because of their irreversible nature, but their actual in vivo functions particularly in brain are not yet well understood. Among the various aspects of protease involvement in neuropathophysiology, our research focuses on two major themes. One is the metabolism of amyloid-βpeptide (Aβ), the cortical deposition of which triggers the pathological cascade leading to AD. Under physiological conditions, Aβ is constantly produced from its precursor and immediately catabolized, whereas dysmetabolism of Aβ seems to lead to pathological deposition upon aging. By elucidating the mechanism of Aβ metabolism, we intend to establish a new approach to prevent AD development by reducing Aβ burdens in aging brains. We also began to establish a novel amyloid imaging approach using a high-power microMRI. The other objective of our research is to define the roles of intracellular proteases, calpains and caspases, in the processes of neuronal dysfunction and degeneration in AD and other neurodegenerative diseases. Because these processes are relatively downstream to Aβ deposition in the disease cascade, we expect the outcome to contribute to AD research in therapeutic rather than preventive terms.

Research Subject

  1. Analysis of Ab-degrading mechanism in brain
  2. Animal models for human brain aging
  3. The role of cellular proteases in aging-associated pathological changes

Related links

  1. RIKEN Brain Science Institute Website_Laboratories PageNew Window

Press release

July 04, 2011
Overlooked peptide reveals clues to causes of Alzheimer's Disease
Highly aggregative and neurotoxic amyloid peptide Aβ43 points the way to new approaches for AD diagnosis and treatment

List of Selected Publications

  1. Nilsson, P., Iwata, N., Muramatsu, S-I., Tjernberg, L.O., Winblad, B., Saido T.C.
    "Gene therapy in Alzheimer's disease -potential for disease modification."
    J. Cell Mol. Med.14, 714-757(2010)
  2. Huang, S.M., Mouri, A., Kokubo, H., Nakajima, R., Suemoto, T., Higuchi, M., Staufenbiel, M., Noda, Y., Yamagushi, H., Nabeshima, T., Saido, T.C., Iwata, N.
    "Neprilysin-sensitive synapse-associated amyloid b peptide oligomers impair neurornal plasticity and cognitive function."
    J. Biol. Chem.,281, 17941-17951(2006).
  3. Huang, S.M., Mouri, A., Kokubo, H., Nakajima, R., Suemoto, T., Higuchi, M., Staufenbiel, M., Noda, Y., Yamagushi, H., Nabeshima, T., Saido, T.C., Iwata, N.
    "Neprilysin-sensitive synapse-associated amyloid b peptide oligomers impair neurornal plasticity and cognitive function."
    J. Biol. Chem.,281, 17941-17951(2006).
  4. Higuchi, M., Iwata, N., Matsuba, Y., Sato, K., Sasamoto, K., and Saido, T.C.
    "19F- and 1H-MRI detection of amyloid-βpeptide in vivo"
    Nature Neurosci., 8, 527-533 (2005).
  5. Saito, T., Iwata, N., Tsubuki, S., Takaki, Y., Takano, J., Huang, S.-H., Suemoto, T., Higuchi, M., and Saido, T.C.
    "Somatostatin regulates brain amyloid β peptide, Aβ42, through modulation of proteolytic degradation"
    Nature Med., 11, 434-439 (2005).
  6. Higuchi, M., Tomioka, M., Takano, J., Shirotani, K., Iwata, N., Masumoto, H., Maki, M., Itohara, S., Saido, T.C.
    "Distinct mechanistic roles of calpain and caspase activation in neurodegeneration as revealed in mice over-expressing their specific inhibitors."
    J. Biol. Chem., 280, 15229-15237(2005).
  7. Takano, J., Tomioka, M., Tsubuki, S., Higuchi, M., Iwata, N. Itohara, S., Maki, M., Saido, T.C
    "Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways: evidence from calpastatin-mutant mice."
    J. Biol. Chem., 280, 16175-16184(2005).
  8. Tsubuki, S., Takaki, Y., and Saido, T.C.:
    "Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Aβ to physiologically relevant proteolytic degradation."
    Lancet, 361, 1957-1958 (2003).
  9. Iwata, N., Tsubuki, S., Takaki, Y., Shirotani, K., Lu, B., Gerard, N.P., Gerard, C., Hama, E., Lee, H.-J., and Saido, T. C.
    "Metabolic regulation of brain Aβ by neprilysin."
    Science, 292, 1550-1552 (2001).
  10. Iwata, N., Tsubuki, S., Takaki, Y., Watanabe, K., Sekiguchi, M., Hosoki, E., Kawashima-Morishima, M., Lee, H.-J., Hama, E., Sekine-Aizawa, Y., and Saido, T. C.
    "Identification of the major Aβ1-42-degrading catabolic pathway in brain parenchyma: Suppression leads to biochemical and pathological deposition"
    Nature Med., 6, 143-151 (2000).
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