Of Mice and Math : a Systems Biology Model for Alzheimer

Title of Document: OF MICE AND MATH: A SYSTEMS BIOLOGY MODEL FOR ALZHEIMER‟S DISEASE Christina Rose Kyrtsos Doctor of Philosophy 2011 Directed By: Dr. John S. Baras Professor Institute for Systems Research Alzheimer‟s disease (AD) is the most prevalent neurodegenerative disorder in the US, affecting over 1 in 8 people over the age of 65. There are several well-known pathological changes in the brains of AD patients, namely: the presence of diffuse beta amyloid plaques derived from the amyloid precursor protein (APP), hyperphosphorylated tau protein, neuroinflammation and mitochondrial dysfunction. Recent studies have shown that cholesterol levels in both the plasma and the brain may play a role in disease pathogenesis, however, this exact role is not well understood. Additional proteins of interest have also been identified (ApoE, LRP-1, IL-1) as possible contributors to AD pathogenesis. To help understand these roles better, a systems biology mathematical model was developed. Basic principles from graph theory and control analysis were used to study the effect of altered cholesterol, ApoE, LRP and APP on the system as a whole. Negative feedback regulation and the rate of cholesterol transfer between astrocytes and neurons were identified as key modulators in the level of beta amyloid. Experiments were run concurrently to test whether decreasing plasma and brain cholesterol levels with simvastatin altered the expression levels of beta amyloid, ApoE, and LRP-1, to ascertain the edge directions in the network model and to better understand whether statin treatment served as a viable treatment option for AD patients. The work completed herein represents the first attempt to create a systems-level mathematical model to study AD that looks at intercellular interactions, as well as interactions between metabolic and inflammatory pathways. OF MICE AND MATH: A SYSTEMS BIOLOGY MODEL FOR ALZHEIMER‟S DISEASE