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Transcription Factor-Mediated Epigenetic Regulation In The Healthy Brain And Neurological Disease, Alexander J. Cammack
Transcription Factor-Mediated Epigenetic Regulation In The Healthy Brain And Neurological Disease, Alexander J. Cammack
Arts & Sciences Electronic Theses and Dissertations
Proper cellular development and function is a complex process established by elaborate gene expression networks. These networks are regulated by epigenetic processes, which alter chromatin states and coordinate the binding of transcription factors (TFs) to regulatory elements (REs), such as enhancers, across the genome to facilitate gene expression. It follows then that a major experimental effort is to profile and understand the binding patterns of TFs to REs in various cellular types and contexts. Critically however, current TF profiling techniques are limited in their abilities to profile TF occupancy in targeted cellular populations and temporal windows, hindering investigations into epigenetic …
Life Of Tau: Oligomerization, Cns Extracellular Clearance And Role As Plasma Biomarker, Tirth Patel
Life Of Tau: Oligomerization, Cns Extracellular Clearance And Role As Plasma Biomarker, Tirth Patel
Arts & Sciences Electronic Theses and Dissertations
The microtubule associated protein tau (MAPT, commonly referred to as tau) is an intrinsically disordered, highly soluble protein predominantly expressed in axons where it binds and stabilizes microtubules. Under normal physiological conditions, soluble monomeric tau is released in the extracellular space in the interstitial fluid (ISF) by neurons. Additionally it undergoes reversible phosphorylation and other extensive modifications inside the cell under the action of a host of enzymes. However in the disease process tau loses this solubility, detaches from microtubules and ultimately migrates to the somatodendritic compartment of the neuron, where it ultimately forms insoluble fibrillar aggregates known as tau …
The Role Of Apolipoprotein E In Regulating Tau Pathogenesis And Neurodegeneration In A Tauopathy Mouse Model, Yang Shi
Arts & Sciences Electronic Theses and Dissertations
APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 increases brain amyloid-β (Aβ) pathology relative to other APOE isoforms. However, whether APOE independently influences tau pathology, the other pathological hallmark of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human APOE knock in (KI) or APOE knockout (KO) background, we show that the presence of human APOE, regardless of APOE isoforms, leads to various degrees of brain atrophy in 9-month old P301S mice, whereas APOE ablation strongly protects against neurodegeneration. In particular, P301S/E4 mice develop …
Exploiting Click-Chemistry And Microfluidics To Map The Neuronal Itinerary Of App Processing And Amyloid-Beta Generation, Namratha Srinivas
Exploiting Click-Chemistry And Microfluidics To Map The Neuronal Itinerary Of App Processing And Amyloid-Beta Generation, Namratha Srinivas
McKelvey School of Engineering Theses & Dissertations
Alzheimer’s disease (AD) is a chronic neurodegenerative disease and is the sixth leading cause of death in the United States with approximately 5.5 million Americans diagnosed with it. The neuropathological hallmark includes extracellular senile plaques and intraneuronal neurofibrillary tangles. Recent GWAS studies have identified genes associated with AD, and have revealed several classes of genes implicated in disease pathogenesis. In particular, three general pathways associated with an increased risk of AD included: 1) cholesterol metabolism, innate immune system, and the membrane trafficking. Our lab has focused on intracellular trafficking as it relates to the processing of amyloid precursor protein (APP), …
The Regulation Of Extracellular Amyloid-Β Levels By Ionotropic Glutamatergic Transmission In An Alzheimer’S Disease Mouse Model, Jane Cecelia Hettinger
The Regulation Of Extracellular Amyloid-Β Levels By Ionotropic Glutamatergic Transmission In An Alzheimer’S Disease Mouse Model, Jane Cecelia Hettinger
Arts & Sciences Electronic Theses and Dissertations
Brain extracellular concentration of the peptide amyloid-β (Aβ) is a major contributor to Alzheimer’s disease (AD) pathogenesis. High Aβ levels in the extracellular space precipitate aggregation of the peptide into soluble and insoluble toxic species. This process begins decades before cognitive impairment and triggers the cascade of pathology that eventually leads to AD. Synaptic activity is key to the regulation of extracellular Aβ levels. Presynaptic activity drives the production of Aβ, while postsynaptic receptor activation exhibits more nuanced regulation. For example, high levels of NMDA receptor (NMDA-R) activation have been shown to decrease Aβ production through the extracellular signal-regulated kinase …