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The novel role of extracellular cardiolipin in microglial activation and neuroinflammation

University of British Columbia

Alzheimer’s disease (AD) is a fatal neurodegenerative disorder characterized by chronic neuroinflammation. Microglia, the immune cells of the brain, become activated in response to pathological stimuli and cellular debris. Once activated, microglia secrete pro-inflammatory mediators, as well as participate in phagocytosis in aims of eliminating the noxious stimuli. Microglial activation is normally beneficial, as it helps maintain homeostatic conditions and regulate the immune status of the brain; however, in AD, microglia become over-activated, which causes the non-specific release of cytotoxic molecules and results in extensive neuronal death. Cardiolipin, a mitochondrial phospholipid implicated in regulating metabolic processes, is significantly reduced in AD brains. Additionally, it has been shown that cardiolipin can be relocated to the outer mitochondrial membrane, as well as to the plasma membrane during various cellular processes. Although the intracellular role of cardiolipin has been well defined, the effects of extracellular cardiolipin on microglial functions implicated in AD pathogenesis have yet to be investigated. The central hypothesis of this thesis proposes that extracellular cardiolipin regulates select microglial functions. I focused on three specific research objectives: 1) to determine whether extracellular cardiolipin induces the phagocytic activity of microglia, 2) to determine whether extracellular cardiolipin affects microglial functions that impact neuronal viability and 3) to determine whether extracellular cardiolipin alters the secretory profile of microglia. By utilizing in vitro cell culture techniques and biological assays with immortalized CNS model cells, as well as primary murine microglia, I demonstrate that extracellular cardiolipin induces the phagocytic activity of microglia, decreases microglia-mediated cytotoxicity towards neurons, as well as alters the secretory profile of activated microglia by reducing the secretion of key inflammatory mediators, including reactive nitrogen and oxygen species, as well as the pro-inflammatory cytokines tumor necrosis factor-alpha and monocyte chemoattractant protein-1. The findings of this study demonstrate that extracellular cardiolipin regulates several microglial functions that potentially impact select aspects of neuroinflammation implicated in AD. Therefore, extracellular cardiolipin may represent a novel therapeutic agent that promotes the clearance of pathological structures, inhibits the extensive neuronal death and alters the secretory profile of over-activated microglia present in neurodegenerative diseases, such as AD.

Text

2017-05-01

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/61409

Biology

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/