Lipid Regulation as a Critical Factor in the Development of Alzheimer's Disease
Alzheimer’s disease (AD) is the most common form of dementia in the United States, representing around eighty percent of all cases. For more than two decades, researchers have been led by the amyloid cascade hypothesis, which assumes that accumulation of the amyloid peptide Aβ, derived by proteolytic processing from the amyloid precursor protein (APP), is the key pathogenic trigger in AD. To date, therapies have largely focused on removing Aβ from the brain, an approach that has produced disappointing clinical outcomes. I present an alternative hypothesis in which Aβ production and aggregation is a symptom of a larger, systemic disease affecting the regulation of lipids, including cholesterol. In addition to assigning a physiological function for APP and Aβ generation, my hypothesis suggests that lipid dysregulation would likely occur early in the disease process, making it an ideal target for identification of disease risk or even intervention. Using a mouse model, I show that expression of APP is involved in the regulation of cholesterol synthesis, endocytosis, and myelination pathways. Using human cell culture models, I demonstrate that fibroblasts and peripheral blood mononuclear cells taken from AD patients show signs of lipid dysregulation, and that neuron-like cells develop this dysregulation when exposed to oxysterols. Finally, I developed and characterized a method of quantifying these detrimental changes using a fluorescence compound, filipin, which could form the basis of a commercial test to evaluate the potential risk of conversion from mild cognitive impairment to AD.
Medical Physiology, Medicine and Health Sciences, Alzheimer Disease - Physiopathology; Alzheimer Disease - Genetics; Lipids - Metabolism; Lipid Regulating Agents; Plaque - Amyloid; Amyloidogenic Proteins; Neural Cell Adhesion Molecules; Nerve Growth Factors; Signal Transduction; Genetic Association Studies, Dementia; Alzheimer's Disease; Amyloid Cascade Hypothesis; Lipid Dysregulation
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