Semester
Summer
Date of Graduation
2026
Document Type
Dissertation
Degree Type
PhD
College
School of Medicine
Department
Exercise Physiology
Committee Chair
Paul D. Chantler
Committee Member
Dharendra Thapa
Committee Member
Randall Bryner
Committee Member
Werner Geldenhuys
Committee Member
Aminata Coulibaly
Abstract
Almost 15 million children aged 2-19 were considered obese in 2017-2020. Childhood obesity puts individuals at risk for high blood pressure, type 2 diabetes, increased blood-brain barrier permeability, and inflammation both in early life and beyond. Obesity can also cause mitochondrial dysfunction by altering the acetylation of proteins involved in energy metabolism. These changes have been documented in preclinical models of obesity in the heart and liver, but acetylation has not been heavily studied in the brain, even though obesity has direct effects on the brain. In middle-aged individuals, obesity has been observed to be a risk factor for both cognitive decline and Alzheimer’s disease (AD). This leads to a paradox in which a high body mass index (BMI) in late life decreases dementia risk, while a high BMI in midlife increases risk for dementia. Few studies have tracked this relationship starting in adolescence to see the impact childhood obesity could have on Alzheimer’s disease and its related dementias (ADRD). ADRD encompasses cognitive decline, functional impairment, and memory loss caused by common forms of dementia like vascular dementia and AD. AD is a multifaceted disease impairing vascular health, glucose metabolism, and mitochondrial function. Dysregulation in these processes can occur as early as 20 years before cognitive deficits appear, further emphasizing the importance of exploring the onset of this disease. However, the exact mechanisms in which these deficits occur are still unknown. In addition, sex differences within outcomes of obesity and AD are often not addressed in the literature. Preclinical models of obesity have shown that different age exposures to a HFD cause sex-dependent effects on weight gain and glucose sensitivity. However, a gap in knowledge remains on how obesity affects the onset of ADRD-related pathologies, such as cerebrovascular and cognitive outcomes, in a sex and age-specific manner. The overarching goal of this dissertation is to comprehensively evaluate how age interacts with cerebrovascular, cognitive, and metabolic outcomes within a preclinical model of obesity and AD. The central hypothesis is that exposure to a HFD early in life will cause metabolic dysregulation that leads to accelerated progression of ADRD pathologies. To help address the gaps in knowledge, the specific aims of this dissertation are to:
Aim 1. Determine the sex dependent differences in HFD induced obesity on cerebrovascular impairment and cognitive decline. We used a C57BL6 murine model (M/F) that was placed on a 60% HFD or normal chow (CON) at 6 months of age. Animals underwent body composition and glucose tolerance testing at 9 months of age. Around 9.5 months, animals were exposed to open-field testing to evaluate locomotion and anxiety-like behavior, the Y-maze to test spatial memory, and novel object recognition to assess retention. At 10 months of age, prior to terminal procedures, cerebral blood flux measurements were taken using laser speckle contrast imaging to evaluate global cerebrovascular health. Sub Aim 1a: Examine the role of lysine acetylation within the brain. For this sub aim, we isolated brain lysates from these animals to run western blotting and immunoprecipitations to detect changes in lysine acetylation of proteins involved in glucose oxidation, beta-oxidation, and the electron transport chain.
Aim 2: Determine how HFD induced obesity affects ADRD progression, through cerebrovascular health and cognition, in male and female 3xTg mice. We used a 3xTg-AD and WT-AD murine model. Mice (M/F) were assigned randomly to a 10% low-fat diet (LFD) or a 60% HFD once weaned at ~21 days. At 4 months of age, these mice underwent behavioral testing to assess the onset of cognitive deficits using open-field, Y-maze, and novel-object measures. At 4.5 months of age, glucose tolerance testing and body composition measurements were run. At 5 months, laser speckle contrast imaging was performed to assess vascular health. These measures were repeated at 8, 8.5, and 9 months. Sub Aim 2a: Determine how isolation of HFD within adolescence and within adulthood affects ADRD progression. In addition to the groups above, we used 3xTg-AD and WT-AD mice (M/F) assigned randomly to LFD or HFD at ~ 21 days, but at 5 months of age, the HFD group was placed onto the LFD (H-L) and the LFD group switched to an HFD (L-H) for the remainder of the study. All measurements stated above were conducted at their respective times on these mice.
Aim 3: Determine how obesity within a 3xtg mouse model affects lysine acetylation and mitochondrial function within the hippocampus and cortex. Hippocampus and cortex lysates were obtained from 9-month-old 3xTg-AD and WT-AD mice exposed to an LFD or HFD since weaning at ~ 21 days. Western blotting and immunoprecipitations were performed to explore the role of lysine acetylation in various metabolic and electron transport chain proteins . In addition, mitochondria were isolated from hippocampus and cortex tissue to measure LCAD and electron transport chain activities.
This work is significant in both obesity and AD, providing a better understanding of how sex and age impact vascular and cognitive outcomes and enabling further exploration of the role of lysine acetylation in the brain.
Recommended Citation
Eminhizer, Nicole Marie, "The Effects of Obesity on Cerebrovascular Health and Metabolism in the Onset of Alzheimer’s Disease" (2026). Graduate Theses, Dissertations, and Problem Reports (ETD). 13378.
https://researchrepository.wvu.edu/etd/13378