Development and application of an in vitro blood-brain barrier model to investigate intravenous immunoglobulin therapy for Alzheimer's disease

Wuest, Diane Marie
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University of Delaware
One of the largest and fastest growing sectors in the global pharmaceutical industry is the development of treatments for diseases of the central nervous system. Unfortunately, current systemically administered medications do not achieve optimum therapeutic efficacy in the brain due to limitations in crossing the blood-brain barrier (BBB). Further research is needed to enhance the understanding of how and what molecules can pass through the BBB, and the creation of an in vitro BBB model is crucial to study the cellular constituents and the dynamic capabilities of the BBB that are difficult or nearly impossible to resolve in vivo. The most prevalent BBB model consists of a monolayer of endothelial cells grown on a porous membrane submerged in the wells of a multi-well plate. The large range of cell types available, cell culture variable set points (species, generation, co-culture setup), and system variable set points (membrane configuration, media composition) has resulted in an expansive number of unique models in the field. The significance of our work lies in presenting an in vitro BBB model based on a rational understanding of model configurations and applicability for advancing brain therapeutic research. The first objective of this research was to construct an optimal in vitro BBB model by statistically screening model parameter set points using primary and immortalized murine endothelial cells and astrocytes. Two sets of sequential screening experiments identified optimal cell culture growth parameter set points and an optimal membrane configuration, which increased model performance 4-fold. The second objective of our work applied this optimized model to investigate BBB phenomena occurring in Alzheimer's disease (AD) and its treatment with intravenous immunoglobulin (IVIG) therapy, a passive immunotherapeutic under investigation for AD in human clinical trials. We quantified IVIG transport into the brain in the presence of Aβ peptides and assessed the subsequent effects on decreasing inflammation. IVIG accumulated in the brain side at physiologically relevant levels and was found to decrease inflammation when low Aβ levels were present. In conclusion, the optimized in vitro BBB model is a valuable tool for efficiently advancing the study of brain diseases and their potential therapeutics.