Stefano L. Sensi

Associate Adjunct Professor, Neurology
School of Medicine

M.D., University G.d'annunzio, Chieti, Italy

Ph.D. in Neuroscience,, University G.d'annunzio, Chieti, Italy

Phone: (949) 824-3838
Fax: (949) 824-1668

University of California, Irvine
2149 Gillespie Neuroscience Facility
Irvine, CA 92697-429
Research Interests
Alzheimer's disease, cerebral ischemia, ALS, excitotoxicity, physiology of glutamate, AMPA, kainate, and NMDA receptors, calcium and zinc dyshomeostasis, acidosis, mitochondria, oxidative stress
Academic Distinctions
Italian National Council for Research-CNR- fellowship for Biotechnology (01/91-01/92)
1999 National Institutes of Health, NIA K01 Award (1999-2004)
2001 UCI –College of Medicine Research Award
2002 UCI – Van den Noort Award for outstanding research by a junior faculty of the Dept. of Neurology
•Research Associate in Neurology - Center for the Study of Neural Injury directed by Dennis Choi, Washington University, St. Louis (02/92-08/97)
•Visiting Researcher in Neurology University of California at Irvine
•Assistant Adjunct Professor in Neurology University of California at Irvine, (07/98-06/02)
•Associate Adjunct Professor in Neurology University of California at Irvine, (07/02- to date)
•Full Adjunct Professor in Neurology, University of Texas Medical Branch, Galveston, USA (12/05- to date)
•Head del Molecular Neurology Unit Center for Excellence on Aging (Ce.SI) University “G. D'Annunzio” (03/2005- to date)
•Associate Professor Rehabilitative Neurology University “G. D'Annunzio”, Chieti- June 2006 to date
•Scientific Coordinator Dept. Basic and Applied Medical Science University “G. D'Annunzio”, Chieti (Nov 2006 to date)
•Dean of the School of Occupational Therapy, Univ “G. D'Annunzio”, Chieti- Nov 2007 to date
Research Abstract
My research interest concerns mechanisms of excitotoxic neurodegeneration, generally of relevance to Alzheimer’s disease, cerebral ischemia, and ALS. Over the years, by using microfluorimetric techniques we focused our studies on evaluating changes in intracellular calcium, pH, and zinc occurring after glutamate receptor overactivation. I gained a particular interest in the complex role of intracellular calcium in determining the fate of neuronal cells after injury. Working on the cascade of events leading to glutamate –triggered neuronal injury we were able to demonstrate how overstimulation of the NMDA type glutamate receptor can lead to a calcium dependent generation of injurious free radicals. Disturbance of acid –base equilibrium is considered to be an important factor in the ischemic neurodegeneration. Working on that front we found that NMDA receptor overactivation to produce a long lasting intracellular acidification, the recovery from which is mainly mediated by bicarbonate dependent systems. We also explored the interaction between AMPA/kainate receptor overstimulation and extracellular acidosis and found that the latter greatly impaired neuronal calcium buffering, suggesting a likely pathogenic mechanism for the enhanced neurotoxicity seen in acidic environments. In the past ten years, because of growing interest in zinc as a key mediator in neurodegeneration, my scientific curiosity has been drawn toward the still largely obscure field of neuronal zinc homeostasis. Taking advantage of the high sensitivity to zinc of traditional fluorescent calcium indicators, we used fluorescent imaging techniques to demonstrate zinc entry through three different routes (NMDA channels, voltage sensitive Ca2+ channels and Ca2+ permeable AMPA/kainate channels (Ca-A/K channels) in response to glutamate exposures. We also showed that zinc permeation through Ca-A/K channels is particularly effective in triggering prolonged mitochondrial dysfunction and reactive oxygen species generation. Finally we started to explore the issue of zinc dyshomeostasis in the context of Alzheimer’s disease. Recent studies of the lab indicate that, in an animal model of the disease (3xTg-AD mice), intracellular concentrations of zinc are altered upon condition of oxidative stress and treatments that restore zinc homeostasis have beneficial neuroprotective and behavioral effects.
DRAGO D, CAVALIERE A, MASCETRA, CIAVARDELLI D, DI ILIO C, ZATTA P, SENSI SL Aluminum modulates effects of ?-Amyloid1-42 on neuronal calcium homeostasis and mitochondria functioning and is altered in a triple transgenic mouse model of Alzheimer’s disease Rejuvenation Res. 2008 Sep 12. [Epub ahead of print]
SENSI S.L., RAPPOSELLI I.G., FRAZZINI V., MASCETRA N. Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of alzheimer’s disease, Exp. Gerontol. May;43(5):488-92. Epub 2007 Nov 12.
Bonanni L, Chachar M, Jover-Mengual T, Li H, Jones A, Yokota H, Ofengeim D, Flannery RJ, Miyawaki T, Cho CH, Polster BM, Pypaert M, Hardwick JM, Sensi SL, Zukin RS, Jonas EA. Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain.
J Neurosci. 2006 26(25):6851-62
Rockabrand E, Slepko N, Pantalone A, Nukala VN, Kazantsev A, Marsh JL,
Sullivan PG, Steffan JS, Sensi SL, Thompson LM. The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet. 2007 16(1):61-77. Epub 2006 Nov 29.
SENSI SL, ROCKABRAND E, CANZONIERO LM.T. Acidosis enhances toxicity induced by kainate and zinc exposure in aged cultured astrocytes. Biogerontology 2006 (5-6):367-374.
SENSI S.L., TON-THAT D., SULLIVAN P.G., JONAS E.A., GEE K.R., KACZMAREK L.K., WEISS J.H. Modulation of mitochondrial function by endogenous Zn2+ pools, PNAS, 100:6157-62, 2003.
SENSI S.L., TON-THAT D., WEISS J.H. Mitochondrial sequestration and Ca2+ dependent release of cytosolic Zn2+ loads in cortical neurons. Neurobiol. Dis.,in press, 2002.
SENSI S.L., YIN H.Z., WEISS J.H. AMPA/kainate receptor-triggered Zn2+ entry into cortical neurons induces mitochondrial Zn2+ uptake and persistent mitochondrial dysfunction. Eur. J. Neurosci.12:3813-8, 2000.
SENSI S.L, YIN H.Z., CARRIEDO S.G., RAO S., J. WEISS. Preferential Zn2+ influx through Ca2+ permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. PNAS 96:2414-9 1999.
SENSI S.L., YIN H.Z, WEISS J.H. Glutamate triggers preferential Zn2+ flux through Ca2+ permeable AMPA channels and consequent ROS production. Neuroreport 10:1723-7, 1999.
Measurement of Intracellular Free Zinc in Living Cortical Neurons: Routes of Entry. J Neurosci. 17: 9554-9564, 1997.
YU S.P., YEH C.H.,. SENSI S.L., GWAG B. J., CANZONIERO L.M.T, FARHANGRAZI Z.S., YING H. S., TIAN M., DUGAN L.L. and CHOI D.W. Neuronal Apoptosis Is Mediated By Enhancement Of Outward Potassium Current And Potassium Efflux. Science 278:114-117, 1997.
Professional Societies
Society for Neuroscience, European Society for Neuroscience
Italian Society of Neurology, American Academy of Neurology
Founding member of the International Society for Zinc Biology
Member of the Steering committee of the International Society for Zinc Biology
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