Abstract

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.

LLU Discipline

Physiology

Department

Basic Sciences

School

School of Medicine

First Advisor

Soriano-Castell, Salvador

Second Advisor

Badaut, Jerome

Third Advisor

Ghribi, Othman

Fourth Advisor

Kirsch, Wolff M.

Fifth Advisor

Pearce, William J.

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2015

Date (Title Page)

6-2015

Language

English

Library of Congress/MESH Subject Headings

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

Subject - Local

Dementia; Alzheimer's Disease; Amyloid Cascade Hypothesis; Lipid Dysregulation

Type

Dissertation

Page Count

204

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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