UBC Theses and Dissertations
Metabolic hormones and physical activity as regulators of brain glial cell functions and neuroimmune status Spielman, Lindsay Joy
Alzheimer’s disease (AD), the most prevalent form of dementia worldwide, is characterized by several cellular hallmarks including chronic neuroinflammation. Glial cells, the immune and support cells of the brain, become activated in response to pathological formations in the AD brain and neuroinflammation occurs as a result. Persistent activation of glial cells can result in chronic neuroinflammation, which can be damaging to brain tissue. The goal of my PhD research project was to elucidate the cellular mechanisms by which certain non-neuronal factors increase the risk of developing AD, such that new treatment options for AD might be identified. My research focused on two risk factors for developing AD: type 2 diabetes mellitus (T2DM) and sedentary (SED) lifestyles. The overarching hypothesis of my thesis is that the metabolic hormone dysregulation as well as reduced physical activity, contribute to AD pathogenesis through neuroimmune mechanisms. I focused on three specific hypotheses: 1) insulin, a metabolic hormone that has reduced functionality in T2DM, regulates the neuroinflammatory response of glia; 2) the incretin hormones glucagon like peptide (GLP)-1 and glucose dependent insulinotropic polypeptide (GIP), which also become dysregulated in T2DM, control several aspects of glial cell function; and 3) physical activity (PA) has an impact on the neuroimmune status of the brain, which is regulated in a monocyte chemoattractant protein (MCP)-1-dependent manner. Using in vitro cell culture techniques, I demonstrate that glial cells express the insulin receptors. I show that insulin could have anti- inflammatory properties in the brain and may protect against glia-mediated neurotoxicity, while GLP-1 and GIP exhibit anti-apoptotic, antioxidant and trophic effects on glial cells. Utilizing in vivo murine studies, I demonstrate that PA can modify glial cell activation and regulate the expression of immune cytokines in the brain. Additionally, I reveal that the neuroimmune status-modifying activity of PA relies partially on MCP-1. I have discovered that insulin, GLP-1, GIP and PA regulate specific aspects of neuroinflammation. Therefore, targeting neuroinflammation may represent viable AD treatment options, which should be explored in future clinical studies.
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