Dr. Paramita Chakrabarty
Dissecting the Role of Inflammation in Neurodegenerative Diseases
Assistant Professor, Neuroscience and CTRND;
Wilder Family Fellow
Post Doc, Neuroscience (Todd Golde) University of Florida, 2009-2011
Post Doc, Neuroscience (Todd Golde), Mayo Clinic College of Medicine, 2005-2009
PhD., Biochemistry, Jawaharlal Nehru University, India, 2002
MSc., Biophysics and Molecular Biology, University of Calcutta, India, 1996
Contact Dr. Chakrabarty
Immune Mediators in Alzheimer’s disease. Cytokines and chemokines have been intimately associated with neurodegenerative pathology in Alzheimer’s disease (AD) type dementia. However, the question remains whether neuroinflammation is the driving force behind the neurodegenerative pathology specifically leading to a self-reinforcing feedback loop to promote Aβ and/or tau pathophysiology in AD. Using recombinant adeno-associated virus mediated gene targeting in the brains of transgenic mice, some key questions that I am attempting to address are 1) the effect of different cytokines, chemokines and pattern recognition receptors on Aβ clearance and tau pathology in mice brain; 2) importance of microglial phenotype in AD type neurodegeneration; and 3) whether overexpression of soluble innate immune receptors in AD mice models can be harnessed as potential disease modifying therapies.
Neuroinflammation and nigrostriatal degeneration. Though neuroinflammation has been associated with Parkinson’s disease, a direct correlation between a specific immune mediator and selective vulnerability of nigrostriatal pathway has not been shown. We have recently demonstrated that Interferon-γ, an inflammatory cytokine, drives massive and selective nigrostriatal degeneration, locomotor impairment and calcinosis of the midbrain while sparing the hippocampus. We are continuing to refine these studies as they will be a crucial next step in a continuum of research that will elucidate the role of IFN-γ in Parkinsonism and provide information regarding IFN-γ signaling pathways as potential therapeutic targets.
Modeling of neurodegeneration using AAV gene targeting in the CNS or “somatic brain transgenesis”
Using recombinant adeno-associated virus mediated gene targeting paradigm, we have established dosage and spatially restricted cytokine gene expression patterns in the CNS that enable us to directly dissect neuroinflammation induced neurodegenerative phenotype that closely resemble the pathophysiology of traditionally constructed transgenic mice lines. Two key questions we are interested in investigating is 1) innate immune system mediated neuronal senescence and neurodegeneration and 2) role of peripheral inflammation in CNS neurodegeneration.
- Das, P, Smithson, LA, Price, RW, Holloway, VM, Levites, Y, Chakrabarty, P and Todd E Golde. Interleukin-1 receptor 1 knockout has no effect on amyloid deposition in Tg2576 mice and does not alter efficacy following Aβ immunotherapy. Journal of Neuroinflammation 2006 July; 3:17.
- Park, KHJ, Hallows, J, Chakrabarty, P, Davies, P and I. Vincent. Conditional neuronal simian virus 40 T antigen expression induces Alzheimer-like tau and amyloid pathology in mice. J Neurosci. 2007 Mar 14;27(11):2969-78.
- Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, Zubair A, Dickson D, Golde T, and Pritam Das. Massive gliosis Induced by Interleukin-6 suppresses A deposition in vivo: Evidence against inflammation as a driving force for amyloid deposition. FASEB J. 2010 February; 24 (2): 548-559
- Chakrabarty, P, Ceballos-Diaz, C,Beccard, A, Janus, C, Dickson, D. Golde, TE, Das, P. IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J. Immunol. 2010 May 1; 184(9): 5333-43
- Chakrabarty, P, Beccard, A, Ceballos-Diaz, C, Das, P, Golde, TE. Hippocampal overexpression of murine TNFα results in attenuation of amyloid deposition in vivo. Molecular Neurodegeneration. 2011 February 16; 6:16
- Chakrabarty, P, Ceballos-Diaz, Lin, W-L, Beccard, A, Jansen-West, K, Janus, C, McFarland, NM, Dickson, D, Das, P, Golde, TE. Interferon-γ induces progressive nigrostriatal degeneration and basal ganglia calcification. Accepted. March 22, 2011. Nature Neuroscience