Mechanistic analysis of iron transport across the blood-brain barrier
McCarthy, Ryan Christopher
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Iron is an essential co-factor in several metabolic processes. In the brain, these processes include myelination, neurotransmitter synthesis, and energy generation. While required for life, iron can also be detrimental if not regulated properly. This is especially true of the brain, where high levels of iron accumulation are often associated with pathological diseases such as Alzheimer's and Parkinson's disease. While it is unclear whether iron mis-regulation is a primary cause or a secondary effect of those diseases, the fact that iron accumulation accompanies their diagnosis is concerning. Evident from the pathologies of Alzheimer's and Parkinson's disease is that, at some level, iron seems to be mismanaged in the brain. Whether this mismanagement is specific to cells of the brain parenchyma or at the level of iron entry into the brain has yet to be realized. Here, I focus on the latter of these two possibilities. At the forefront of iron entry into the brain is a group of brain microvascular endothelial cells (BMVEC) and their neighboring astrocytes which, together, form the blood-brain barrier (BBB). This dissertation will focus on recent advances regarding developmental iron accumulation by the brain, focusing on the transport of iron through the BMVEC of the BBB. I provide a description of the iron regulatory proteins which may be involved in BMVEC iron trafficking, and then define several models of BMVEC iron regulation. First, the plausible mechanisms of BMVEC iron uptake are discussed. Next, I demonstrate the mechanism of iron efflux from BMVEC. I then discuss how this mechanism of BMVEC iron efflux is closely regulated by secreted factors from neighboring astrocytes. In this context I present a working model for brain iron uptake with respect to the neurovascular unit of the adult brain. Finally, I propose BMVEC iron is likely involved in the aggregation of amyloid-beta; peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease. The models presented in this dissertation diagram the intrinsic iron regulatory properties at and beyond the BBB.