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Alzheimer’s disease (AD) is the most common cause of dementia, occurs predominantly in those over the age of 65 and impacts many aspects of daily life (Mastroeni et al., 2011). A key pathological hallmark of AD pathogenesis is the accumulation of brain amyloid beta peptides which aggregate in plaque formations, and are accompanied by inflammation and focal demyelination (Galasko & Montine, 2010; Mitew et al., 2010). Alzheimer’s disease progression manifests as clinical symptoms including memory loss, social dysfunction, and alterations in executive function, following a loss of neurons and synapses in respective brain regions (Arnáiz & Almkvist, 2003; Bondi, Edmonds, & Salmon, 2017; Klimova, Maresova, Valis, Hort, & Kuca, 2015). While neuron loss and inflammation in Alzheimer’s disease has been extensively researched, there has been limited study on myelin changes. In the central nervous system, the oligodendrocytes are myelin-forming glial cells which mature from oligodendrocyte precursor cells (OPCs) by membrane and cytoskeletal alterations. They provide metabolic support for neurons and mediate continual remodelling of myelin sheaths, which occurs throughout life in response to learning (Funfschilling et al., 2012; Kaplan et al., 2001; Young et al., 2013). Previous studies of Alzheimer’s disease, including animal models, show loss of myelin in the vicinity of amyloid plaques (Bartzokis, 2011; Dean 3rd et al., 2017; Mitew et al., 2010). Plaque forming amyloid beta peptides are generated from cleavage of the amyloid precursor protein (APP) by β-secretase and γ-secretase enzymes resulting in a number of peptides; however Aβ40 and Aβ42 are suggested to be key in AD progression, with Aβ42 being more hydrophobic and fibrillogenic and most commonly present within the amyloid plaques (Selkoe, 2001). Several mutations in the APP and γ-secretase genes have been described in familial AD. These mutations result in increased amyloid levels in the brain and have been utilized in human studies and animal models to further our understanding of AD pathogenesis. However, there have been a limited number of studies investigating how increased brain amyloid affects myelination in the brain, including generation of new oligodendrocyte lineage cells and maturation of OPCs. This thesis seeks to understand the role that increased levels of amyloid beta peptides have on the maturation of oligodendrocytes, and the capacity for myelination induced by learning a new task. Previous work in our laboratory has demonstrated demyelination in cortical layer V in mouse models and human cases of AD (Mitew et al., 2010). However, the cause and effect of amyloid on oligodendrocyte lineage cells cannot be directly studied in humans. Rodent models represent useful paradigms for investigating the effects of increased brain amyloid on specific cell types. Therefore, in this study, I first investigated myelin and oligodendrocyte lineage cells in a rat model of induced amyloidosis. For this study, I used the TgF344-AD rat model, which overexpresses human APP with the Swedish mutation (KM670/671NL; APP\(_{swe}\)) as well as the human Presenilin-1 Δ exon 9 mutation (PS1ΔE9), both driven by the mouse prion promoter. Previous studies have demonstrated amyloid plaque formation in the hippocampus and cortex between 6 and 26 months of age and tau pathology at 16 months in this model (Cohen et al., 2013). I first characterized alterations in the TgF344-AD rat model of amyloidosis, at 18-25 months of age when extensive amyloid plaques were present. I hypothesised that the presence of elevated Aβ would alter the myelination of axons in these animals. I quantitated the total oligodendrocyte numbers, in the cortex, hippocampus and corpus callosum of transgenic and wildtype (WT) animals using immunohistochemistry and examined the axons in the corpus callosum using electron microscopy. Analysis of changes to total oligodendrocyte numbers by two-tailed student t-test demonstrated significant (p

After injury, infection, or major operations a number of predictable metabolic responses occur. It has been proposed that the cytokine tumor necrosis factor (TNF)/cachectin is a primary mediator of these host responses. To test this hypothesis, we studied 16 tumor-bearing humans with normal renal and hepatic function, who received 24-hour continuous intravenous infusions of escalating doses of recombinant TNF (4 to 636/micrograms/m2/24 h). Serial measurements were made of vital signs and plasma concentrations of TNF, interleukin-1, adrenocorticotropic hormone, cortisol, iron, glucose, and C-reactive protein. Low doses of TNF had minimal metabolic effects, but infusions of greater than or equal to 545 micrograms/m2/24 hr (n = 8) resulted in fever, pituitary, and stress hormone release and acute phase changes. These alterations were compared with the changes that occurred in healthy humans (n = 13) receiving intravenous bolus injections of Escherichia coli endotoxin (4 ng/kg). TNF infusion in doses greater than or equal to 545 micrograms/m2/24 hr produced peak plasma TNF concentrations and metabolic responses that were similar to those after endotoxin injection. Interleukin-1 concentrations remained basal after TNF or endotoxin administration. TNF may represent the primary afferent signal that initiates many of the metabolic responses associated with sepsis and endotoxemia.

The neuroendocrine response that occurs after operation, trauma, or infection is essential for maintaining homeostasis within the host. Corticotropin-releasing hormone, (CRH), arginine vasopressin (AVP), and products of the cyclooxygenase pathway have been proposed as possible mediators of the pituitary-adrenal response. We studied the relationship between the induction of these mediators and the onset of the neuroendocrine response in healthy male volunteers receiving one of two standard provocative stimuli: (1) Escherichia coli endotoxin (4 ng/kg intravenously) and (2) hypoglycemia induced by insulin (0.15 units/kg intravenously). Additional subjects receiving these stimuli were pretreated with the cyclooxygenase inhibitor ibuprofen, 1600 mg orally. Serial measurements were made of circulating concentrations of CRH, AVP, adrenocorticotropic hormone, cortisol, and catecholamines. A sudden rise in circulating AVP (but not CRH) concentrations preceded the onset of all other responses after both stimuli. The prevention of this surge of AVP after endotoxin by ibuprofen was associated with blockade of the neuroendocrine response. These data demonstrate that two independent pathways are available for stimulation of the stress response. After both stimuli, peripheral AVP (but not CRH) levels may mirror alterations that occur within the central nervous system.