Molecular Mechanisms of Aging and Alzheimer’s Disease
Date of Award
Doctor of Philosophy (PhD)
Interdepartmental Neuroscience Program
Alzheimer’s Disease (AD) is a major public health crisis. AD is a progressive neurodegenerative disease and is the leading cause of dementia worldwide. Currently, there are no disease-modifying drugs available for the treatment of AD. Although autosomal dominant genetic forms of the disease are very rare, they are the foundation for many models of study; in part, because the etiology of the far more common, sporadic AD, remains unknown. While the cause of most AD cases is undetermined, age is a well-known, significant risk factor. The work presented in this thesis relies on studies of non-genetically modified aging rodents and monkeys to better understand how aging naturally impacts regions of the brain, namely the prefrontal cortex (PFC), that are vulnerable to AD-related degeneration. The final chapter of this thesis expands to a proteomic analysis of human cerebrospinal fluid (CSF) aimed at more fully and reliably characterizing AD- and age-related changes in the brain. Overall, we found age-related upregulation of the neuroimmune complement signaling molecule, C1q, in the PFC of animal models and were able to monitor various components of the complement signaling cascade in the CSF assay. These studies may help us better understand the role of complement signaling in age- and AD-related synaptic loss. Additionally, in the animal models, age-related dysregulation of calcium-cAMP-PKA signaling was found to correlate with early-stage AD tau phosphorylation and cognitive impairment. We expanded our analysis of age-related tau phosphorylation by developing a phosphoproteomic approach which identified two additional sites of age-related phosphorylation increase on tau (S235 and S309). These results shed important insight into potential pathways of resistance to AD and future therapeutic avenues.
Leslie, Shannon Noble, "Molecular Mechanisms of Aging and Alzheimer’s Disease" (2021). Yale Graduate School of Arts and Sciences Dissertations. 364.