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 ar... read moree not 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
- Component ID:
- tufts:23417
- To Cite:
- DCA Citation Guide EndNote
