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Lindhout, Ivan Andrew

University of British Columbia

Microglia provide immune defense in the central nervous system (CNS) through functions that include cytokine and cytotoxin secretion and phagocytosis. However, in several CNS disorders such as Alzheimer’s disease, aberrant activation of microglia causes decreased phagocytic activity and increased neurotoxicity due to the release of cytotoxic reactive oxygen (ROS) and nitrogen (RNS) species and pro-inflammatory cytokines. The growth factor interleukin (IL)-34 and neurotrophins (NTs) brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), as well as the proneurotrophin proBDNF are important for trophic signaling and regulation of survival and apoptosis in neurons. The effects of these compounds are mediated through the IL-34 receptor, colony-stimulating factor-1 receptor, and the NT receptors (NTRs), tropomyosin-receptor kinase (Trk)A, TrkB, and p75NTR. These growth factors and proBDNF also have profound CNS effects by binding to their receptors on other cell types, including microglia. IL-34, BDNF, and NGF have been shown to have therapeutic potential by reducing microglial immune activation. However, the large size of BDNF and NGF prevents them from penetrating the blood-brain barrier easily. Therefore, small molecules were developed to circumvent these issues while retaining the ability to activate NTR signaling pathways, including the TrkA ligand GK-2, TrkB ligand GSB-106, and p75NTR ligand LM11A-31. In my thesis work, I addressed knowledge gaps surrounding the effects of these three ligands as well as proBDNF and IL-34 on microglial neuroinflammatory functions. Chapter three demonstrates that IL-34 increased phagocytic activity of unstimulated and stimulated microglia, decreased ROS release by primed microglia-like cells, reduced monocyte chemoattractant protein (MCP)-1 secretion by stimulated microglia-like cells, and raised RNS production by unstimulated microglia. In chapter four, I show that LM11A-31 and proBDNF decreased the release of ROS by microglia-like cells and proBDNF increased the phagocytic activity of microglia. Chapter five shows that GK-2 decreased the release of ROS by primed microglia-like cells and the phagocytic activity of stimulated microglia. GSB-106 lowered the production of ROS in unprimed and primed microglia-like cells and the secretion of MCP-1 in stimulated microglia-like cells. Therefore, my research showed that IL-34, LM11A-31, proBDNF, GK-2, and GSB-106 regulate select immune processes of microglia and microglia-like cells.

Text

2024-06-10

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88451

Biology

University of British Columbia

UBCO

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