Dr. Yona Levites
Role of Amyloid in Neurodegenerative Disorders – Prevention, Treatment, and Modeling
Assistant Professor, Neuroscience and CTRND
Post Doc, Neuroscience (T. Golde), Mayo Clinic College of Medicine, 2003-2008
Ph.D., Neuroscience and Pharamacology, Technion, Israel, 1998-2002
B.S., Food Science and Biotechnology, Technion, Israel, 1991-19995
Contact Dr. Levites
Adeno-associated viruses (AAV) have been extensively used for targeted gene expression in numerous organs across species. We utilize an innovative approach of AAV mediated gene delivery and expression in the rodent brain in order to test prevention and treatment paradigms as well as develop new models of amyloidosis and neurodegeneration. Somatic brain transgenesis allows time and cost effective validation of a various array of mediators of CNS function.
- Development of immunotherapeutic tools for treatment and prevention in AD models.
- Numerous strategies to prevent Abeta aggregation and accumulation are being evaluated as ways to treat or prevent AD. Recently we and other have shown data supporting the hypotheses that targeting Abeta assemblies may be a better target for AD immunotherapy. We hypothesized that single chain variable fragments (scFv) that recognize generic amyloid will effectively attenuate pathology in Alzheimer’s Disease mouse model. Our goal is to develop a high affinity binding agent (scFv, as well as full length antibody) that will bind amyloid and prevent amyloid toxicity in animal models and, potentially, in clinic.
- The mechanisms underlying the abnormal phosphorylation and accumulation of Tau protein in AD remain unclear, but one of the possibilities is that it might be due to its conformational changes. Our objective is to generate and characterize stable intracellular anti-Ptau scFvs (intrabodies), and determine their effect on the pathological accumulation of tau in neurons, as well on neurofibrillary tangle formation and neuron loss, using AAV mediated trunsduction to the brain of tau-transgenic mice.
- Mechanism of anti-Abeta immunotherapy.
Additionally, we have been attempting to dissect potential mechanisms involved in Abeta vaccination strategies for the therapy of AD using transgenic mouse models.
- Development of novel models of neurodegenerative diseases.
Another path of research we are pursuing is development of animal models that more closely than the existing ones resemble Alzheimer’s disease processes in the human brain. We deliver individual beta-amyloid protein fragments, non-Abeta amyloidogenic peptides as well as other proteins suggested to either directly or indirectly interact with APP to rodent brain and determine whether these models develop a brain pathology similar to Alzheimer’s.
- Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, Zubair AC, Dickson D, Golde TE, Das P. Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 2010 Feb;24(2):548-59. Epub 2009 Oct 13.
- Golde TE, Das P, Levites Y. Quantitative and mechanistic studies of abeta immunotherapy. CNS Neurol Disord Drug Targets.2009; ;8(1):31-49.
- Kim J, Miller VM, Levites Y, West KJ, Zwizinski CW, Moore BD, Troendle FJ, Bann M, Verbeeck C, Price RW, Smithson L, Sonoda L, Wagg K, Rangachari V, Zou F, Younkin SG, Graff-Radford N, Dickson D, Rosenberry T, Golde TE. BRI2 (ITM2b) inhibits Abeta deposition in vivo. J Neurosci. 2008 ; 28(23):6030-6.
- Laifenfeld D, Patzek LJ, McPhie DL, Chen Y, Levites Y, Cataldo AM, Neve RL. Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis. J Neurosci. 2007 Jul 4;27(27):7141-53.
- Levites Y, Das P, Smithson L, Golde T. Anti-A Antibodies Work at Substochiometric Levles to Alter APP Transgenic Mice, FASEB Journal, 2006 Dec;20(14):2576-8.
- Levites Y.; Jansen K.; Smithson L; Holloway V.M.; Das P.;Golde T.E., Intracranial AAV mediated delivery of anti-pan Abeta, Abeta40 and Abeta42 scFvs attenuates plaque pathology in APP mice, J. Neurosci., 2006; 26(46):11923-8.
- P Das, L A Smithson, R W Price, V M Holloway, Y Levites, P Chakrabarty, and T E Golde. Interleukin-1 receptor 1 knockout has no effect on amyloid deposition in Tg2576 mice and does not alter efficacy following Abeta immunotherapy. J Neuroinflammation. 2006; 3: 17.
- Levites Y, Das P, Price RW, Rochette MJ, Kostura LA, McGowan EM, Murphy MP, Golde TE.Anti-Abeta42- and anti-Abeta40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J Clin Invest. 2005 Dec 8; [Epub ahead of print]
- Silvia Mandel, Edna Grünblatt, Peter Riederer, Manfred Gerlach, Yona Levites and Moussa B.H. Youdim and. (2003). Neuroprotective Strategies in Parkinson’s disease: An Update on Progress. CNS Drugs. 2003;17(10):729-62.