Laboratory for Proteolytic Neuroscience

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. The other objective is to define the roles of intracellular proteases, calpains and caspases, and also of autophagy in the processes of neuronal dysfunction and degeneration in AD and other neurodegenerative diseases. Because these processes are relatively down-stream to Aβ deposition in the disease cascade, we expect the outcome to contribute to AD research in therapeutic rather than preventive terms. We also aim to identify the mechanisms (pathways), by which Aβ amyloidosis causes tauopathy and neurodegeneration. For this purpose, we generated 2nd generation mouse models of AD, which overproduce Aβ42 without overexpressing amyloid precursor protein. These models will also be useful for the search of biomarkers.

Research Subjects

• Analysis of Abeta-degrading mechanism in brain
• Animal models for human brain aging
• The role of cellular proteases in aging-associated pathological changes
• Search of biomarker(s) for brain aging

Publications

1. Higuchi, M., Iwata, N., Matsuba, Y., Takano, J., Suemoto, T., Maeda, J., Ji, B., Ono, M., Staufenbiel, M., Suhara, T., Saido, T.C.:
   "Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology."
   FASEB J., 26, 3, 1204-1207 (2012).
2. Saito, T., Suemoto, T., Brouwers, N., Sleegers, K., Funamoto, S., Mihira, M., Matsuba, Y., Yamada, K., Nilsson, P., Takano, J., Nishimura, M., Iwata, N., Van Broeckhoven, C., Ihara, Y., Saido, T.C.:
   "Potent amyloidogenicity and pathogenicity of Aβ43. "
   Nat. Neurosci.,14, 1023-1032 (2011).
3. Takano, J., Mihira, N., Fujioka, R., Hosoki, E., Chishti, A.H., Saido, T.C.:
   "Vital role of the calpain-calpastatin system for placental integrity-dependent embryonic survival."
   Mol. Cell Biol., 31, 4097-4106 (2011).
4. 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)
5. 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).
6. 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).
7. 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).
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).