Investigating the role of diet and exercise on age-related neuroinflammation and neuronal health
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 a... read morere 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
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