Investigating the role of diet and exercise on age-related neuroinflammation and neuronal health
Graham, Leah.
2017
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Abstract: Age-related cognitive decline and neurodegenerative diseases such as Alzheimer's disease (AD) involve complex interaction of both genetic and environmental risk factors. A growing number of studies identify a westernized diet, obesity, cardiovascular disease and physical inactivity through middle age as major risk factors for cognitive decline and AD, but the underlying mechanisms are no... read moret known. Therefore, to investigate the links between diet, age-related cognitive decline and neurodegenerative diseases we used a diet that mimics diets commonly consumed in western cultures (WD). In C57BL/6J (B6) mice and a widely used mouse model of AD (B6.APP/PS1, B6.APBTg), we showed that chronic consumption of the WD caused obesity, increases in neuroinflammation and vascular susceptibility along with an age-dependent cognitive decline. To understand the mechanisms by which the WD caused cognitive decline, we performed transcriptional profiling on WD fed B6 mice and age-matched controls. Genes associated with three major processes - myelination, microglial function and vascular health - were differentially expressed (DE) in WD- compared to chow-fed mice. From the gene expression data, we hypothesized that myelin integrity was perturbed in WD-fed mice. This was confirmed using immunofluorescence, electron microscopy and western blotting and was most striking in the major white matter tracts of the central nervous system (CNS). Given this novel finding, we worked with collaborators at Indiana University to determine the effects of obesity and high BMI on white matter tracts in humans. We identified white matter dysfunction in AD-susceptible brain regions of obese, human subjects, confirming the relevance of our findings in mice. To determine the mechanisms by which a WD leads to white matter dysfunction, we used multiple short-term diet studies to assess microglial activity and vascular health, as we hypothesized these could be key drivers. There was a significant increase in reactive microglia in the white matter tracts of WD-fed obese mice surrounding areas vulnerable to neurovascular unit damage and astrocyte reactivity. Further, activated microglia were phagocytosing myelin, which supports a model where myelin turnover - a normal process that aids neuronal health during aging, is perturbed by a western diet leading to excess clearance of myelin. Finally, we identified that voluntary running prevented diet-associated myelin loss and cognitive decline, and suppressed many of the neuroinflammatory signatures induced by the WD alone. Importantly, the protective effect of exercise occurred despite a significant increase in weight. Overall, my studies identified a mechanism by which a western diet/obesity can causes white matter dysfunction and cognitive decline.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Genetics.
Advisor: Gareth Howell.
Committee: Greg Cox, Phil Hinds, Kevin Mills, Dave Serreze, Elissa Chesler, and David Loane.
Keywords: Biology, Genetics, and Molecular biology.read less - ID:
- br86bf73f
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