The Role of Cholesterol in Alzheimer's disease Pathogenesis: Preliminary Report
C. Kyrtsos and J.S. Baras
Proceedings of the Biomedical Engineering Society (BMES 2010), Austin, Texas, October 6-9, 2010.
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting 1 in 8 individual over the age of 65. A growing body of evidence is suggesting that cholesterol levels in both the brain and the plasma may play significant roles in AD pathogenesis; however, the exact nature of this role is currently not well understood. Building on previous experiments, we have approached this problem using two, complementary methods- a systems biology model for brain metabolic networks that is based on empirical data gathered from in vivo experiments. The main goal of this study was to determine the effect that decreased brain cholesterol had on the level of beta amyloid (the key protein implicated in AD pathogenesis) and the extent of neurodegeneration observed. To achieve this, APPSwe/PS1 double transgenic mice were treated twice daily with simvastatin (a cholesterol-lowering drug) for a period of 2 or 10 weeks. The effects of the decreased brain cholesterol levels on APP and beta amyloid processing, as well as apoE and LRP-1 expression levels was studied using Western blotting and immunohistochemistry techniques, respectively. The extent of neurodegeneration was determined via immunohistochemical staining of hippocampal slices for synaptic density and neuron viability. The weights between key nodes in the systems biology model were updated to account for the observed experimental results.