Tsuneya Ikezu, M.D., Ph.D.
M.D., University of Tokyo Faculty of Medicine
Ph.D., University of Tokyo Graduate School of Medicine
Laboratory: Laboratory of Molecular NeuroTherapeutics
Research Interests: Dr. Ikezu’s Laboratory of Molecular NeuroTherapeutics primarily focuses on Neuroimmunology and how the innate immune-related molecules in the central nervous system (CNS) influences the pathology and progression of select neurodegenerative disorders e.g. Alzheimer’s Disease (AD). Further, the lab investigates pharmacological means to suppress the innate immune response in the CNS with the goal of enhancing neuronal protection and minimizing collateral damage from an activated immune response in the CNS. Specifically we are investigating the role of the signaling cytokine IL-4/10/CD200 and its potential anti-inflammatory/neuroprotective role between microglia and both neurons and astrocytes during active CNS inflammation. Further, we are exploring IL-4/10/CD200 as a potential therapeutic in chronic inflammatory states within the CNS, such as seen in Alzheimer’s disease, to minimize neuronal cell loss.
A second focus of our lab is the investigation of tau-tubulin kinases (TTBK1 and 2) and their role in hyper-phosporylating tau protein leading to the formation of tau and alpha-synuclein tangles within neurons, a key pathology observed in AD, Amyotrophic lateral sclerosis (ALS)/Lou Gehrig’s Disease, Spinocerebellar Ataxia, and Frontotemporal Dementia (FTD). We are currently performing a cutting-edge drug discovery program to identify potential inhibitors to TTBK1 with the goal of identifying potential new therapeutic(s) that could prevent the formation of tangle formation within neurons in these neurodegenerative states. We primarily use novel gene-targeted/transgenic mouse models to characterize our studies by employing a mix of assays including: standard biochemical assays, gene expression analyses, tissue cultures from both primary cells and cell lines, immunohistochemistry, gene-delivery vectors, and animal behavioral testing.
Selected Peer-Reviewed Publications
Kiyota T, Ingraham KO, Swan RJ, Jacobsen MT, Andrew SJ, Ikezu T. AAV serotype2/1-mediated gene delivery of anti-inflmmatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther.2011 Sep 15. doi: 10.1038/gt.2011.126 [Epub ahead of print] PMID:21918553.
Kiyota T, Ingraham KL, Jacobsen MT, Xiong H, Ikezu T. FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer’s disease and has therapeutic implications for neurocognitive disorders.Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1339-48. Epub 2011 Oct 31. PMID:22042871
Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T. Interferon-g and tumor necrosis factor-a regulate amyloid-b plaque deposition and b-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 170:680-92 (2007)
Flaherty DP, Walsh SM, Kiyota T, Dong Y, Ikezu T, Vennerstrom JL. Polyfluorinated Styrylbenzene b-Amyloid Plaque Binding Ligands. J Med Chem 50:4986-92 (2007).
Gorantla S, Lui J, Sneller H, Dou H, Smith L, Ikezu T, Holguin A, Volsky DJ, Poluektova L, and Gendelman HE. Glatiramer Acetate Immunization Modulates Glial Function and Protects Neurons in a Murine Model of HIV-1 Encephalitis. J Immunol 179:4345-56 (2007).
Yamamoto M, Ramirez SH, Sato S, Kiyota T, Cerny RL, Kaibuchi K, Persidsky Y, and Ikezu T. Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells. Am J Pathol 172:521-33 (2008) PMCID: PMC2312373
Yamamoto M, Kiyota T, Walsh SM, Liu J, Kipnis J, Ikezu T. Cytokine-mediated inhibition of fibrillar amyloid-b peptide degradation by human mononuclear phagocytes. J Immunol 181:3877-86 (2008) PMCID: PMC2603577
Buescher JL, Duan F, Sun J, Price R, Ikezu T. OTK18 levels in plasma and cerebrospinal fluid correlate with viral load and CD8 T-cells in normal and AIDS patients. J Neuroimmune Pharmacol 3:230-5 (2008) PMCID: PMC2581637
Buescher JL, Martinez LB, Sato S, Okuyama S, and Ikezu T. YY1 and FoxD3 regulate antiretroviral zinc finger protein OTK18 promoter activation induced by HIV-1 infection: Implications in brain perivascular macrophage-specific OTK18 gene expression. J Neuroimmune Pharmacol Epub ahead of print (2008) PMCID: PMC2680142
Martinez LB, Walsh SM, Jacobsen MT, Sato S, Wiederin J, Ciborowski P, and Ikezu T. Calpain and proteasomal regulation of antiretroviral zinc finger protein OTK18 in human macrophages: Visualization in live cells by intramolecular FRET. J Neuroimmune Pharmacol Epub ahead of print (2008) PMCID: PMC2644346
Xu J, Ikezu T. The comorbidity of HIV-associated neurocognitive disorders and Alzheimer’s disease: a foreseeable medical challenge in post-HAART era. J Neuroimmune Pharmacol Epub ahead of print (2008) PMCID: PMC2682636
Sato S, Xu J, Okuyama S, Martinez LB, Walsh SM, Jacobsen MT, Swan R, Schlautman JD, Ciborowski P, and Ikezu T. Spatial learning impairment, enhanced Cdk5/p35 activity, and down-regulation of NMDA receptor in transgenic mice expressing tau-tubulin kinase 1. J Neurosci 28:14511-21 (2008) PMC journal – in process
Kiyota T, Yamamoto M, Schroder B, Jacobsen MT, Swan RJ, Lambert MP, Klein WL, Gendelman HE, Ransohoff RM, Ikezu T. AAV1/2-mediated CNS Gene Delivery of Dominant-negative CCL2 Mutant Suppresses Gliosis, beta-amyloidosis, and Learning Impairment of APP/PS1 Mice. Mol Ther 17(5):803-809 (2009) PMCID: PMC2709991
Kiyota T, Yamamoto M, Xiong H, Lambert MP, Klein WL, Gendelman HE, Ransohoff RM, Ikezu T. CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction. PLoS One. 4:e6197 (2009)
Tokuraku K, Marquardt M, Ikezu T. Real-time imaging and quantification of amyloid-beta peptide aggregates by novel quantum-dot nanoprobes. PLoS One.4:e8492 (2009)
Xu J, Sato S, Okuyama S, Swan RJ, Jacobsen MT, Strunk E, and Ikezu T. Tau-tubulin kinase 1 enhances pre-fibrillar tau aggregation, spatial learning impairment, and motor neuron degeneration in P301L FTDP-17 tau mutant mice. FASEB J [Epub ahead of print]
Kiyota T, Okuyama S, Swan RJ, Jacobsen MT, Gendelman HE, Ikezu T. CNS expression of anti-Inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J [Epub ahead of print]
Xu J, Tsutsumi K, Tokuraku K, Estes KA, Hisanaga SI, Ikezu T. Actin interaction and regulation of cyclin-dependent kinase 5/p35 complex activity. J Neurochem. 2010 May 21. [Epub ahead of print]
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