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.
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.
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.
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.
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.
D. Ourdev, A. Schmaus and S. Kar (2019) Kainate receptor activation enhances amyloidogenic processing of APP in astrocytes. Mol. Neurobiol. 56: 5095-5110.
A. Kodam*, D. Ourdev*, M. Maulik, J. Hariharakrishnan, M. Banerjee, Y. Wang and S. Kar (2019) A role for astrocyte-derived amyloid β peptides in the degeneration of neurons in an animal model of Temporal Lobe Epilepsy. Brain Pathol. 29: 28-44. (*equal contributions)
J. Chung, G. Phukan, D. Vergote, A. Mohamed, M. Maulik, M. Stahn, R.J. Andrew, G. Thinakaran, E.I. Posse de Chaves and S. Kar (2018) Endosomal-lysosomal cholesterol sequestration by U18666A treatment differentially regulates APP metabolism in normal and APP overexpressing cells. Mol. Cell. Biol. 38: e00529-17.
B.V. Foroutanpay*, J. Kumar*, S.G. Kang, N. Danaei, D. Westaway, V.L. Sim and S. Kar (2018) The effects of N-terminal mutations of β-amyloid peptide aggregation and toxicity. Neuroscience 379: 177-188. (*equal contributions)