Date Approved

6-2013

Document Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

Department

Cell Biology

College

Graduate School of Biomedical Sciences

First Advisor

Robert Nagele, PhD

Committee Member 1

John Pastorino, PhD

Committee Member 2

Venkat Venkataraman, PhD

Subject(s)

Blood-Brain Barrier, Tight Junctions, Diabetes Mellitus, Alzheimer Disease, Disease Models, Animal, Risk Factors

Disciplines

Disease Modeling | Laboratory and Basic Science Research | Medical Cell Biology | Medicine and Health Sciences | Molecular Biology | Nervous System Diseases | Physiological Processes

Abstract

Studies have shown that the vascular risk factors common to diabetes mellitus and hypercholesterolemia are also risk factors for Alzheimer’s disease (AD). It is currently unknown how these diseases are associated with AD, but they may cause a leak in the blood brain barrier (BBB), which is one of the hallmarks of AD. In this preliminary study, over 150 pig brain slides were tested for the expression levels of tight junction proteins occludin and claudin V in the BBB microvasculature. There were three groups of pig brains used in this study namely, control pigs, pigs with diabetes mellitus and hypercholesterolemia (DMHC), and DMHC pigs treated with darapladib, a drug being developed by GlaxoSmithKline for the treatment of atherosclerosis. The results showed changes in the level of expression of occludin and claudin V in the DMHC treated pigs compared to control pigs. The results also revealed expressional changes of claudin V and occludin in the drug treated pigs compared to control pigs. Therefore, these results appear to suggest that long-term diabetes mellitus and hypercholesterolemia conditions may have an effect on the expression of tight junction proteins found in the BBB. This may provide a plausible explanation for the observed increase in BBB permeability in DMHC pigs and also a mechanistic link that may explain why diabetes is now considered a major risk factor for AD.

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