Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS), characterized by an immune-mediated demyelination and neurodegeneration of the CNS, for which there is no adequate therapeutic intervention. The disease is characterized by both local inflammation from resident cells in the brain and by the infiltration of leucocytes from the periphery. MS is primarily considered a T cell-mediated autoimmune disease, at least in the initiation phase, with self reactivity against several myelin-derived antigens. Other cell types involved in the disease are dendritic cells, macrophages, and microglia. The enzyme glycogen synthase kinase-3 (GSK3) is a critical regulator of a variety of cellular functions, and we and others now report that it is a major regulator of inflammation. Dysregulation of GSK3 is associated with several neurodegenerative disorders associated with inflammation, such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. We found that mice pretreated with the GSK3 inhibitor lithium are completely protected from development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and that lithium treatment after onset of clinical disease ameliorates EAE and inhibits relapses. Conversely, in knockin mice expressing constitutively active GSK3, EAE developed more rapidly and was more severe. These data provides strong evidence that GSK3 is proinflammatory in EAE, however the mechanism by which GSK3 regulates inflammation in the CNS is unresolved. We found that the recovery from EAE in lithium treated mice is associated with reduced microglia activation, and decreased demyelination. We also demonstrated that treatment of mice in vivo with the GSK3 inhibitor lithium, at doses that parallel doses used in humans, inhibited antigen-specific T cell proliferation and proinflammatory cytokine from splenocytes of lithium-treated compared to untreated immunized mice. Based on these data our central hypothesis is that GSK3 promotes proinflammatory cascades in EAE. To test this hypothesis, we will: 1) expand and follow up our initial findings by examining the consequences of modulating GSK3 in vivo by pharmacological and genetic approaches on the development and progression of acute and relapsing/remitting EAE;2) perform ex-vivo studies to address the mechanism of lithium-mediated protection to test the hypothesis that the major target of lithium attenuation of EAE in mice are dendritic cells and microglia. Our proposed studies will set the framework for therapeutic targeting of GSK3 for treatment of MS and other neuroinflammatory diseases. Since lithium is already a drug approved by FDA for treatment of psychiatric disorders, the outcome of this proposal can lead to rapid evaluations in human patients. Furthermore, with the availability of more specific GSK3 inhibitors that are being developed, this study is likely to be the basis for their use in the treatment of MS, and other neurodegenerative diseases with inflammatory components.

Public Health Relevance

The research proposed in this application will provide better understanding of the inflammatory events that lead to neurological damage in experimental autoimmune encephalomyelitis, and by extension in multiple sclerosis and other inflammatory diseases of the central nervous system. This project is very relevant to public health because inflammation is linked not only to multiple sclerosis, but also to several other neurodegenerative, and psychiatric diseases. The identification of the enzyme GSK3 as a central regulator of the inflammatory processes in the brain will open a possibility for developing more specific targeted therapy for treatment of multiple sclerosis and other neurological diseases that involve inflammatory components.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Utz, Ursula
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University of Alabama Birmingham
Schools of Medicine
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