Ryan, Scott D2013-11-082013-11-0820082008Source: Dissertation Abstracts International, Volume: 70-04, Section: B, page: 2290.http://hdl.handle.net/10393/29595http://dx.doi.org/10.20381/ruor-13041Aberrant glycerophosphocholine metabolism is associated with neuronal loss in multiple neurodegenerative diseases. In addition to being central to activation of apoptosis, aberrations in steady state levels of the platelet activating factor (PAF) family of glycerophospholipids influence production and degradation of multiple other bioactive lipids making PAF a promising target for disease intervention. In this thesis, I show that concentrations of C16-PAF, and its immediate metabolite C16- lyso-PAF, are elevated in post-mortem Alzheimer disease and transgenic (TgCRND8) mouse temporal cortex. It has been assumed that activation of the PAF G-protein coupled receptor (PAFR) was required for PAF-induced apoptosis. Here, I show that C16-PAF triggers neuronal apoptosis in neurons devoid of PAFR and that PAFR expression protects neurons from C16-PAF but not C18-PAF demonstrating that carbon chain length at the sn-1 position has significant impact on biological activity. As PAFR is only expressed in discrete neuronal populations yet PAF-induced neuronal loss is widespread, both PAFR-dependent and PAFR-independent mechanisms must be involved. This thesis sought to elucidate downstream PAFR-independent signalling pathways in neurodegenerative disease. I delineated a novel signal transduction pathway whereby rising concentrations of C16-PAF induce endoplasmic reticulum (ER) stress and activate Cdk5 and Gsk3beta, resulting in the phosphorylation of microtubule associated proteins that elicits apoptosis in human neurons devoid of PAFR. Finally, to intervene in PAF toxicity, I identified a novel PAF inhibitor (orsellinic acid) that protects neurons from C16-PAF without impacting on PAFR-mediated neuroprotection. Together, these data provide new mechanistic insight into how aberrant lipid metabolism compromises neuronal function in Alzheimer disease.281 p.enChemistry, Biochemistry.Thesis