Date of Graduation
School of Medicine
James W. Simpkins
Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disease afflicting millions of people in the United States alone and is the only one of the top leading causes of morbidity and mortality with no effective disease-modifying therapies. It is the most common form of dementia, affecting one in three people over the age of 85. While the hallmarks of the disease include accumulation of beta-amyloid-based extracellular plaques and hyperphosphorylated tau-based intracellular neurofibrillary tangles, treatment strategies centered on removing or mitigating these components of AD have all failed in humans. Mitochondrial dysfunction has been increasingly recognized as an early and consistent pathological feature of AD. Many questions remain, however, regarding the onset of mitochondrial dysfunction, its importance to disease progression, and its amenability to treatment to slow or halt progression of AD. Using a triple-transgenic mouse model of AD, we studied mitochondrial abnormalities in neurons during the earliest and latest stages of AD pathology. The studies presented in this dissertation show that mitochondrial dysfunction possibly begins even during neural development and could be amenable to correction with activation of the sigma-1 receptor, an intracellular chaperone molecule that enhances mitochondrial function among other neuroprotective effects. We also show that neuronal mitochondrial number and structure are largely preserved across multiple brain areas at the very latest stages of AD. The studies presented herein add to the growing body of evidence of mitochondrial involvement in AD pathophysiology and suggest possible avenues for clinical translation of mitochondrially-targeted therapies for AD.
Cavendish, John Zachary, "Mitochondrial Aspects of Neuronal Pathology in Triple-Transgenic Alzheimer’s Disease Mice" (2021). Graduate Theses, Dissertations, and Problem Reports. 4024.
Animal Experimentation and Research Commons, Biochemical Phenomena, Metabolism, and Nutrition Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Cell Biology Commons, Laboratory and Basic Science Research Commons, Molecular and Cellular Neuroscience Commons, Nervous System Diseases Commons, Neurosciences Commons