Date of Award

4-30-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Edward Campbell

Abstract

An estimated 55 million people worldwide suffer from dementia, with the prevalence expected to drastically increase in the coming years as the population ages. Alzheimer’s disease (AD) is the most common form of dementia and the substantial burden associated with AD has been recognized as a growing public health issue. Despite significant advancements in uncovering the mechanisms which play a role in disease pathology, there is currently no cure or effective treatments. AD is highly complex and multifactorial, with accumulation of misfolded protein, oxidative stress, and inflammation among the numerous etiological processes implicated in disease pathogenesis. While genetic risk factors are more difficult to address, modifiable risk factors are attractive targets for the prevention and delay in progression of cognitive decline. Mounting evidence suggests metabolic dysregulation may be a key factor in the onset and progression of neurodegenerative disorders, with type 2 diabetes mellitus conferring a nearly 2-fold greater risk of developing dementia. Diet is known to influence the development and progression of metabolic disorders such as diabetes, and there is literature to suggest that dietary modifications are beneficial in addressing cognitive decline. Inflammation is a hallmark feature of both metabolic and neurodegenerative diseases, and in recent years the inflammasome has emerged as a potential link between these pathologies. Inflammasomes are multiprotein oligomers that regulate innate immune inflammatory responses through caspase-1 cleavage and have been implicated in various diseases. However, the effect diet has on modulating the inflammasome in the central nervous system (CNS) remains poorly understood. This study examined a high glycemic index diet and a ketogenic diet to establish whether the source and quantity of carbohydrates in the diet can influence systemic inflammation, CNS inflammasome activation, and determine if sex specific sensitivities exist for any of these variables. We utilized a transgenic caspase-1 biosensor mouse model to monitor caspase-1 activation in vivo in the context of a healthy animal and a double transgenic AD mouse model expressing the biosensor to examine how diet may influence AD progression. In non-AD mice, we found that the ketogenic diet caused metabolic derangements in both male and female mice, but that the high glycemic index diet in males and the ketogenic diet in females led to increased central nervous system inflammasome activation. These findings correlated with elevated IL-1β and TNF levels in the serum and the emergence of anxiety-like phenotypes. We observed that although high-glycemic index diet and the ketogenic diet induced significant changes in the fecal microbiomes, these changes were not significantly linked with changes in caspase-1 activity or glucose tolerance. In AD mice, we similarly found that the ketogenic diet induced glucose intolerance in male and female mice. However, we observed no changes in brain inflammasome activation with the experimental diets in either sex. Behavior phenotyping revealed no differences in motor function, spatial learning, or anxiety in males or females. A significant decrease in associative learning and memory was noted in female AD mice on the KD, while males showed no changes in response to diet. Nonetheless, our findings are important as researchers and clinicians consider using dietary interventions for preventative purposes. Further, larger studies are necessary to elucidate the mechanisms of our findings.

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