Investigating Lipidomic Determinants of Cognitive Impairment in Mouse Models of Alzheimer’s Disease

Abstract

Alzheimer’s disease is an insidious neurodegenerative disease that affects millions of people worldwide. Currently, there are no determinants that can accurately predict the onset cognitive decline in AD. This thesis investigates and defines changes in the lipidome that are linked to symptomatic onset and cognitive impairment in mouse models of AD. Using a targeted lipidomic approach employing high performance liquid chromatography electrospray ionization tandom mass spectrometry, direct biochemical assessments, and behavioural evaluation, I was able to (a) profile and quantify cortical and hippocampal glycerophosphocholine and glycerophosphoethanolamine metabolites and signaling molecules in the APPSwe/PS1dE9 and the N5 TgCRND8 murine models of AD and (b) associate changes in lipid metabolism with learning and memory impairment. I demonstrate that glycerophosphocholine metabolism in the cortex but not the hippocampus is altered at symptomatic onset in both mouse models. These same metabolic changes were seen in younger animals exposed to chronic intermittent hypoxia, an environmental risk factor that accelerates their phenoconversion. In fully impaired transgenic mice, I defined metabolic changes associated with disease progression. To further assess the impact of sex, another risk factor of Alzheimer’s disease cognitive decline, I characterized an AD model of sex-specific cognitive resistance. I demonstrated that transgenic males but not females exhibit behavioural indices of cognitive reserve when tested in the Morris Water Maze. Using this mouse line, I then investigated how measures of learning and memory associated with glycerophosphocholine and glycerophosphoethanolamine metabolism. I identified increases in critical glycerophosphoethanolamine metabolites linked to spatial learning and memory impairment in the cortex of N5 TgCNRD8 mice and demonstrated that these changes could be predicted by profiling the plasma glycerophosphoethanolamine lipidome. Taken together, this thesis links glycerophospholipid metabolism to the onset and progression of learning and memory impairment in experimental models of AD and provides the first evidence that changes in cortical lipid metabolism can be predicted by changes in the plasma lipidome.