Dr. Satyabrata Kar
PhD: Histochemistry, Hammersmith Hospital, University of London, United Kingdom
Post-doctoral training: Neuroscience, Douglas Hospital, McGill University, Montreal, Canada
Division of Neurology, Departments of Medicine and Psychiatry, Centre for Prions and Protein Folding Diseases Neuroscience and Mental Health Institute, Faculty of Medicine & Dentistry
M. Maulik, K. Peake, J. Chung, Y. Wang, J.E. Vance and S. Kar (2015) APP overexpression in absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer’s disease. Hum. Mol. Genetics .
Y. Wang, V. Buggia-Prevot, M.E. Zavorka, R.C. Bleackley, R.G. MacDonald, G. Thinakaran and S. Kar (2015) Overexpression of the insulin-like growth factor-II receptor increases β-amyloid production and affects cell viability. Mol. Cell. Biol.
A. Amritraj, Y. Wang, T.J. Revett, D. Vergote, D. Westaway and S. Kar (2013) Role of cathepsin D in U18666A-induced neuronal cell death: potential implication in Niemann Pick Type C disease pathogenesis.J. Biol. Chem.
M. Maulik, B. Ghoshal, J. Kim, Y. Wang, J. Yang, D. Westaway and S. Kar (2012) Mutant human APP exacerbates pathology in a mouse model of NPC and its reversal by a β-cyclodextrin.Hum. Mol. Genetics
Confronting the cause of Neurodegeneration in the Alzheimer's Disease brain
Our laboratory works on two complementary research projects. The first project is designed to address the underlying cause of neurodegeneration in the brain of Alzheimer’s disease (AD) patients. The second project is aimed to study the role of insulin-like growth factors (IGFs) in the normal brain and their implications in AD pathology. The overall objective of these two projects is to establish the cause of the preferential vulnerability of neurons in AD and to determine how these neurons could be protected.
1)β-amyloid and AD: AD is characterized by the presence of tau-positive neurofibrillary tangles, β-amyloid (Aβ)-containing neuritic plaques and the loss of neurons in selected regions of the brain. Accumulated evidence suggests that Aβ accretion may initiate neurodegeneration, leading to the development of AD. The brain regions that are severely affected include cortex and hippocampus, whereas striatum and cerebellum are relatively spared. We have previously reported that Aβ-related peptides can regulate brain neurotransmitter release and trigger degeneration of neurons by activating specific signaling mechanisms. More recently using genetics, cellular and biochemical approaches we are evaluating whether Aβ-induced leakage of lysosomal enzymes may underlie the cause of selective neurodegeneration observed in AD brains.
2)Cholesterol, APP processing and AD:
We have earlier reported that sequestration of cholesterol within the endosomal-lysosomal compartments can decrease longevity, impair motor and cognitive functions, exacerbate glial pathology and trigger degeneration of neurons in transgenic mice overexpressing mutant human APP. Additionally, we show that cholesterol sequestration can influence APP/Aβ metabolism and enhance neuronal vulnerability to oxidative stress. More recently, we have been working to define the mechanisms by which cholesterol buildup within the endosomal-lysosomal system can regulate APP processing leading to increased production/ deposition of Aβ peptides in AD brains.
3)Astrocytes and AD:
Although neurons are the major source of Aβ in the brain, activated astrocytes associated with neuritic plaques of the AD brain are known to accumulate Aβ which correlates positively with local tissue damage. Since normal astrocytes do not express Aβ, it is of interest to determine how Aβ peptides gather in activated astrocytes and evaluate their contribution to AD pathology. Using a variety of approaches including a newly developed line of transgenic mice we are currently evaluating how activation astrocytes can contribute to the production/clearance of Aβ-related peptides and the role of astrocytic Aβ in the development of AD pathology.
4)IGFs and AD:
: IGFs (i.e., IGF-I & IGF-II) are pleiotropic polypeptides with structural and functional homologies to the hormone insulin. The biological responses of IGFs are mediated by interactions with specific IGF-I and IGF-II receptors that are differentially regulated during development and following lesion-induced brain injury. We are currently evaluating how IGF-II by interacting with its single transmembrane domain IGF-II receptor can regulate neurotransmitter release involved in cognition and its implications in AD pathology.