RIKEN BRAIN SCIENCE INSTITUTE (RIKEN BSI)

Faculty Detail / 研究室詳細

Takaomi C. Saido, Ph.D.

- We aim to elucidate the mechanism of brain aging that leads to the onset of Alzheimer's Disease.

Proteolytic Neuroscience

Senior Team Leader

Aging, Alzheimer's disease, Proteolysis

Takaomi C. Saido

Research Area

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.

Kinetic relationships between production, degradation inside the brain, and transport out of the brain.
The steady-state Aβ (Aβ42) level in the brain, [Aβ] ([Aβ42]), is primarily a function of the APP level, [APP], the rate constants for production, K1, in-brain degradation, K2, and out-of-brain transport, K3.

Selected Publications View All

  1. 1

    Guix FX, Sannerud R, Berditchevski F, Arranz AM, Horré K, Snellinx A, Thathiah A, Saido T, Saito T, Rajesh S, Overduin M, Kumar-Singh S, Radaelli E, Corthout N, Colombelli J, Tosi S, Munck S, Salas IH, Annaert W, and De Strooper B: "Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments.", Molecular Neurodegeneration Affiliated with:, 541(7638)(12:25 DOI: 10.1186/s13024-017-0165-0) (2017)

  2. 2

    Saito T, Matsuba Y, Yamazaki N, Hashimoto S, and Saido TC: "Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression.", J Neurosci, 36(38), 9933-6 (2016)

  3. 3

    Masuda A, Kobayashi Y, Kogo N, Saito T, Saido TC, and Itohara S: "Cognitive deficits in single App knock-in mouse models.", Neurobiol Learn Mem (2016)

  4. 4

    Nagata K, Kiryu-Seo S, Tamada H, Okuyama-Uchimura F, Kiyama H, and Saido TC: "ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis.", Acta Neuropathol (2016)

  5. 5

    Nilsson P, Loganathan K, Sekiguchi M, Winblad B, Iwata N, Saido TC, and Tjernberg LO: "Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice.", Proteomics (2015)

  6. 6

    Nilsson P, Sekiguchi M, Akagi T, Izumi S, Komori T, Hui K, Sörgjerd K, Tanaka M, Saito T, Iwata N, and Saido TC: "Autophagy-Related Protein 7 Deficiency in Amyloid β (Aβ) Precursor Protein Transgenic Mice Decreases Aβ in the Multivesicular Bodies and Induces Aβ Accumulation in the Golgi.", Am J Pathol (2014)

  7. 7

    Sörgjerd KM, Zako T, Sakono M, Stirling PC, Leroux MR, Saito T, Nilsson P, Sekimoto M, Saido TC, and Maeda M: "Correction to Human Prefoldin Inhibits Amyloid-β (Aβ) Fibrillation and Contributes to Formation of Nontoxic Aβ Aggregates.", Biochemistry, 53(21), 3520 (2014)

  8. 8

    Nilsson P, Saito T, and Saido TC: "New Mouse Model of Alzheimer's.", ACS Chem Neurosci (2014)

  9. 9

    Nilsson P, and Saido TC: "Dual roles for autophagy: Degradation and secretion of Alzheimer's disease Aβ peptide.", Bioessays (2014)

  10. 10

    Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, and Saido TC: "Single App knock-in mouse models of Alzheimer's disease.", Nat Neurosci (2014)

  11. 11

    Nilsson P, Loganathan K, Sekiguchi M, Matsuba Y, Hui K, Tsubuki S, Tanaka M, Iwata N, Saito T, and Saido TC: "Aβ Secretion and Plaque Formation Depend on Autophagy.", Cell Rep (2013)

  12. 12

    Iwata N, Sekiguchi M, Hattori Y, Takahashi A, Asai M, Ji B, Higuchi M, Staufenbiel M, Muramatsu S, and Saido TC: "Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice.", Sci Rep, 3, 1472 (2013)

  13. 13

    Kakiya N, Saito T, Nilsson P, Matsuba Y, Tsubuki S, Takei N, Nawa H, and Saido TC: "Cell-surface expression of the major Aβ degrading enzyme, neprilysin, depends on phosphorylation by MEK and dephosphorylation by protein phosphatase 1a.", J Biol Chem (2012)

  14. 14

    Takano J, Mihira N, Fujioka R, Hosoki E, Chishti AH, and Saido TC: "Vital role of the calpain-calpastatin system for placental-integrity-dependent embryonic survival.", Mol Cell Biol, 31(19), 4097-106 (2011)

  15. 15

    Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, and Saido TC: "Potent amyloidogenicity and pathogenicity of Aβ43.", Nat Neurosci, 14(8), 1023-32 (2011)

  16. 16

    Nilsson P, Iwata N, Muramatsu S, Tjernberg LO, Winblad B, and Saido TC: "Gene therapy in Alzheimer's disease - potential for disease modification.", J Cell Mol Med, 14(4), 741-57 (2010)

  17. 17

    Takano J, Tomioka M, Tsubuki S, Higuchi M, Iwata N, Itohara S, Maki M, and Saido TC: "Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: evidence from calpastatin mutant mice.", J Biol Chem, 280(16), 16175-84 (2005)

  18. 18

    Higuchi M, Iwata N, Matsuba Y, Sato K, Sasamoto K, and Saido TC: "19F and 1H MRI detection of amyloid beta plaques in vivo.", Nat Neurosci, 8(4), 527-33 (2005)

  19. 19

    Saito T, Iwata N, Tsubuki S, Takaki Y, Takano J, Huang SM, Suemoto T, Higuchi M, and Saido TC: "Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation.", Nat Med, 11(4), 434-9 (2005)

  20. 20

    Tsubuki S, Takaki Y, and Saido TC: "Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation.", Lancet, 361(9373), 1957-8 (2003)

Press Releases View All