Takaomi Saido, Ph.D.

Research Overview

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.

Main Research Fields

Biological Sciences

Related Research Fields

Biology / Medicine, Dentistry & Pharmacy

Keywords

• Alzheimer’s disease
• amyloid
• tau
• neuroinflammation
• neurodegeneration

Selected Publications

1. Iwata N, Tsubuki S, Sekiguchi M, Watanabe-Iwata K, Matsuba Y, Kamano N, Fujioka R, Takamura R, Watamura N, Kakiya N, Mihira N, Morito T, Shirotani K, Mann DM, Robinson AC, Hashimoto S, Sasaguri H, Saito T, Higuchi M, Saido TC.
   "Metabolic resistance of Aβ3pE-42, a target epitope of the anti-Alzheimer therapeutic antibody, donanemab"
   Life Sci Alliance. 2024 Sep 30;7(12):e202402650.
   doi: 10.26508/lsa.202402650
2. Sato K, Sasaguri H, Kumita W, Sakuma T, Morioka T, Nagata K, Inoue T, Kurotaki Y, Mihira N, Tagami M, Manabe RI, Ozaki K, Okazaki Y, Yamamoto T, Suematsu M, Saido TC, Sasaki E.
   "Production of a heterozygous exon skipping model of common marmosets using gene-editing technology"
   Lab Anim (NY). 2024 Sep;53(9):244-251.
   doi: 10.1038/s41684-024-01424-0
3. Watamura N, Kakiya N, Fujioka R, Kamano N, Takahashi M, Nilsson P, Saito T, Iwata N, Fujisawa S, Saido TC.
   "The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain"
   Sci Signal. 2024 Aug 6;17(848):eadk1822.
   doi: 10.1126/scisignal.adk1822
4. Sato K, Watamura N, Fujioka R, Mihira N, Sekiguchi M, Nagata K, Ohshima T, Saito T, Saido TC, Sasaguri H.
   "A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide"
   J Biol Chem. 2021 Sep;297(3):101004.
   doi: 10.1016/j.jbc.2021.101004
5. Hashimoto S, Matsuba Y, Kamano N, Mihira N, Sahara N, Takano J, Muramatsu SI, Saido TC, Saito T.
   "Tau binding protein CAPON induces tau aggregation and neurodegeneration"
   Nat Commun. 2019 Jul 1;10(1):2964.
   doi: 10.1038/s41467-019-10990-8
6. Sasaguri H, Nagata K, Sekiguchi M, Fujioka R, Matsuba Y, Hashimoto S, Sato K, Kurup D, Yokota T, Saido TC.
   "Introduction of pathogenic mutations into the mouse Psen1 gene by Base Editor and Target-AID"
   Nat. Commun., 2018 Jul 24;9(1):2892.
   10.1038/s41467-018-05262-w
7. Nagata K, Takahashi M, Matsuba Y, Okuyama-Uchimura F, Sato K, Hashimoto S, Saito T, Saido TC.
   "Generation of App knock-in mice reveals deletion mutations protective against Alzheimer's disease-like pathology"
   Nat Commun., 2018 May 4;9(1):1800.
   doi: 10.1038/s41467-018-04238-0
8. Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC.
   "Single App knock-in mouse models of Alzheimer's disease"
   Nat Neurosci., 2014 May;17(5):661-3.
   10.1038/nn.3697
9. 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, Saido TC.
   "Potent amyloidogenicity and pathogenicity of Aβ43"
   Nat Neurosci., 2011 Jul 3;14(8):1023-32.
   10.1038/nn.2858
10. Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, Gerard C, Hama E, Lee HJ, Saido TC.
    "Metabolic regulation of brain Abeta by neprilysin"
    Science, 2001 May 25;292(5521):1550-2.
    10.1126/science.1059946