Tsuneya Ikezu, M.D., Ph.D.

Ikezu1209_3 (3)
Professor of Pharmacology & Experimental Therapeutics and Neurology
Department of Pharmacology

M.D., University of Tokyo Faculty of Medicine
Ph.D., University of Tokyo Graduate School of Medicine

Laboratory: Laboratory of Molecular NeuroTherapeutics

Research Interests:

Research Interests: The Laboratory of Molecular NeuroTherapeutics mainly focuses on neuroimmune cell-mediated regulations of neuronal function, neurogenesis, neuroinflammation, and neurodegeneration. In particular, we are interested in 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, frontotemporal dementia and autism spectrum disorders.

The current studies include pharmacological means to suppress the propagation of tau protein mouse models. We have created adeno-associated virus-mediated expression of tau protein, which shows spread from neurons to neurons in microglia and exosome synthesis-dependent manner (Asai H, et al Nat Neurosci 2015). AV summary.

A second focus of our lab is the investigation of inflammation-related autism spectrum disorders. Maternal immune activation refers to the systemic infection during the first or second trimester of pregnancy. This is a major risk of autism spectrum disorders. We hypothesize that maternal immune activation develops chronic alternation in microglial homeostatic function, which results in neurodevelopmental abnormality and autism-like phenotypes in animal models.

We use multiple biological reagents and techniques for our studies: tissue culture of neurons, neural stem cells and microglia, custom AAV vectors, stereotaxic intracranial injection, immunohistochemistry, in situ hybridization, electrophysiology and animal behavior.

Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T. Nat Neurosci. 2015 Oct 5. doi: 10.1038/nn.4132.

The anti-inflammatory glycoprotein, CD200, restores neurogenesis and enhances amyloid phagocytosis in a mouse model of Alzheimer’s disease. Varnum MM, Kiyota T, Ingraham KL, Ikezu S, Ikezu T. Neurobiol Aging. 2015 Aug 1. pii: S0197-4580(15)00393-0. doi: 10.1016/j.neurobiolaging.2015.07.027.

miR-155 Is Essential for Inflammation-Induced Hippocampal Neurogenic Dysfunction. Woodbury ME, Freilich RW, Cheng CJ, Asai H, Ikezu S, Boucher JD, Slack F, Ikezu T. J Neurosci. 2015 Jul 1;35(26):9764-81. doi: 10.1523/JNeurosci.4790-14.2015. PubMed PMID: 26134658; PubMed Central PMCID: PMC4571507.

PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. Jun G, Asai H, Zeldich E, Drapeau E, Chen C, Chung J, Park JH, Kim S, Haroutunian V, Foroud T, Kuwano R, Haines JL, Pericak-Vance MA, Schellenberg GD, Lunetta KL, Kim JW, Buxbaum JD, Mayeux R, Ikezu T, Abraham CR, Farrer LA. Ann Neurol. 2014 Sep;76(3):379-92. doi: 10.1002/ana.24219.

Tau-tubulin kinase. Ikezu S, Ikezu T. Front Mol Neurosci. 2014 Apr 28;7:33. doi: 10.3389/fnmol.2014.00033. eCollection 2014. Review. PubMed PMID: 24808823; PubMed Central PMCID: PMC4009424.

The spectrum of disease in chronic traumatic encephalopathy. McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC. Brain. 2012 Dec 2.

The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Varnum MM, Ikezu T. Arch Immunol Ther Exp (Warsz). 2012 Aug;60(4):251-66. doi: 10.1007/s00005-012-0181-2. Epub 2012 Jun 19. Review.

Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. Vanderweyde T, Yu H, Varnum M, Liu-Yesucevitz L, Citro A, Ikezu T, Duff K, Wolozin B. J Neurosci. 2012 Jun 13;32(24):8270-83. doi: 10.1523/JNEUROSCI.1592-12.2012.

Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, Upreti C, Kracht JM, Ericsson M, Wojnarowicz MW, Goletiani CJ, Maglakelidze GM, Casey N, Moncaster JA, Minaeva O, Moir RD, Nowinski CJ, Stern RA, Cantu RC, Geiling J, Blusztajn JK, Wolozin BL, Ikezu T, Stein TD, Budson AE, Kowall NW, Chargin D, Sharon A, Saman S, Hall GF, Moss WC, Cleveland RO, Tanzi RE, Stanton PK, McKee AC. Sci Transl Med. 2012 May 16;4(134):134ra60. doi: 10.1126/scitranslmed.3003716.

FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer’s disease and has therapeutic implications for neurocognitive disorders. Kiyota T, Ingraham KL, Jacobsen MT, Xiong H, Ikezu T. Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1339-48. doi: 10.1073/pnas.1102349108. Epub 2011 Oct 31. Erratum in: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21282. PMCID: PMC3241747.

AAV serotype2/1-mediated gene delivery of anti-inflmmatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Kiyota T, Ingraham KO, Swan RJ, Jacobsen MT, Andrew SJ, Ikezu T. Gene Ther.2011 Sep 15. doi: 10.1038/gt.2011.126 [Epub ahead of print] PMID:21918553.

Interferon-g and tumor necrosis factor-a regulate amyloid-b plaque deposition and b-secretase expression in Swedish mutant APP transgenic mice. Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu TAm J Pathol 170:680-92 (2007)

Polyfluorinated Styrylbenzene b-Amyloid Plaque Binding Ligands. Flaherty DP, Walsh SM, Kiyota T, Dong Y, Ikezu T, Vennerstrom JL. J Med Chem 50:4986-92 (2007).

Copolymer-1 induces adaptive immune anti-inflammatory glial and neuroprotective responses in a Murine Model of HIV-1 Encephalitis.Gorantla S, Lui J, Sneller H, Dou H, Smith L, Ikezu T, Holguin A, Volsky DJ, Poluektova L, and Gendelman HE. J Immunol 179:4345-56 (2007).

Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells. Yamamoto M, Ramirez SH, Sato S, Kiyota T, Cerny RL, Kaibuchi K, Persidsky Y, and Ikezu T.Am J Pathol 172:521-33 (2008) PMCID: PMC2312373

Cytokine-mediated inhibition of fibrillar amyloid-b peptide degradation by human mononuclear phagocytes. Yamamoto M, Kiyota T, Walsh SM, Liu J, Kipnis J, Ikezu T. J Immunol 181:3877-86 (2008) PMCID: PMC2603577

OTK18 levels in plasma and cerebrospinal fluid correlate with viral load and CD8 T-cells in normal and AIDS patients. Buescher JL, Duan F, Sun J, Price R, Ikezu TJ Neuroimmune Pharmacol 3:230-5 (2008) PMCID: PMC2581637

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. Buescher JL, Martinez LB, Sato S, Okuyama S, and Ikezu T.  J Neuroimmune Pharmacol 4(1): 103-15. (2008) PMCID:  PMC2680142

Calpain and proteasomal regulation of antiretroviral zinc finger protein OTK18 in human macrophages: Visualization in live cells by intramolecular FRET. Martinez LB, Walsh SM, Jacobsen MT, Sato S, Wiederin J, Ciborowski P, and Ikezu T.  J Neuroimmune Pharmacol 4(1):116-28. (2008) PMCID:  PMC2644346

The comorbidity of HIV-associated neurocognitive disorders and Alzheimer’s disease: a foreseeable medical challenge in post-HAART era. Xu J, Ikezu TJ Neuroimmune Pharmacol 4(2):200-12. (2009) PMCID:  PMC2682636

Spatial learning impairment, enhanced Cdk5/p35 activity, and down-regulation of NMDA receptor in transgenic mice expressing tau-tubulin kinase 1.  Sato S, Xu J, Okuyama S, Martinez LB, Walsh SM, Jacobsen MT, Swan R, Schlautman JD, Ciborowski P, and Ikezu T. J Neurosci 28:14511-21 (2008) PMC journal – in process

AAV1/2-mediated CNS Gene Delivery of Dominant-negative CCL2 Mutant Suppresses Gliosis, beta-amyloidosis, and Learning Impairment of APP/PS1 Mice. Kiyota T, Yamamoto M, Schroder B, Jacobsen MT, Swan RJ, Lambert MP, Klein WL, Gendelman HE, Ransohoff RM, Ikezu T.  Mol Ther 17(5):803-809 (2009)  PMCID:  PMC2709991

CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction. Kiyota T, Yamamoto M, Xiong H, Lambert MP, Klein WL, Gendelman HE, Ransohoff RM, Ikezu T.PLoS One. 4:e6197 (2009)

Real-time imaging and quantification of amyloid-beta peptide aggregates by novel quantum-dot nano probes. Tokuraku K, Marquardt M, Ikezu T.  PLoS One.4:e8492 (2009) PMCID: PMC2794548.

Tau-tubulin kinase 1 enhances pre-fibrillar tau aggregation, spatial learning impairment, and motor neuron degeneration in P301L FTDP-17 tau mutant mice. Xu J, Sato S, Okuyama S, Swan RJ, Jacobsen MT, Strunk E, and Ikezu TFASEB J (2010) 24(8):2904-15.

CNS expression of anti-Inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice. Kiyota T, Okuyama S, Swan RJ, Jacobsen MT, Gendelman HE, Ikezu TFASEB J 24(8):3093-102. (2010) PMCID: PMC2909296

Actin interaction and regulation of cyclin-dependent kinase 5/p35 complex activity.  Xu J, Tsutsumi K, Tokuraku K, Estes KA, Hisanaga SI, Ikezu T.J Neurochem. 116(2):192-204. (2011) PMCID: PMC 297558.

Office: 72 East Concord St.,L-606B
Email: tikezu@bu.edu
Phone: 617-414-2658
Fax: 617-638-4329