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Insight into the Regulation of the Blood-Brain Barrier

Silbak, Sadiq H
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308364

Abstract Details

2015, MS, University of Cincinnati, Medicine: Immunology.
The blood-brain barrier (BBB) is composed of endothelial cells, astrocyte end-feet, and perictyes. However, the relative contributions of each constituent to the BBB remains largely unknown. Conversely, the BBB has been shown to be involved in various physiological roles, including signal transduction and selective permeability. The selective permeability of the BBB restricts the milieu of antibodies, humoral neurotransmitters, and other blood plasma components from causing harm to the central nervous system (CNS) and impairing its functions. Alterations in the BBB are thought to arise as a result of neurological disorders. However, increasing scientific evidence suggests that the dysregulation and disruption of the BBB can contribute to the pathogenesis of a subset of neurological disorders and diseases including multiple sclerosis (MS) and neurofibromatosis type 1 (NF1). Understanding the role the immune system plays in the context of such disorders is in its infancy; the pathophysiology of disorders, such as MS, are not entirely understood. There are two primary schools of thought on how some neurological disorders that involve the immune system progress. The first model, the inside-out model, states that cytodegeneration of the neural tissue leads to the opening of the BBB and release of antigenic proteins and lipids. Subsequently, the immune system mounts a response further propagating the neural tissue damage and giving rise to symptoms. The second model, the outside-in model, states that the individual possess auto-reactive T cells which release cytokines and soluble mediators, such as nitric oxide, causing the BBB to open. Consequently, the immune cells transmigrate into the CNS, which results in neuroinflammation. Hence, the enigmatic question of whether BBB dysfunction precedes cellular infiltration or results from neuroinflammation has yet to be answered. NF1 animal models have been used to study a variety of neurological processes, such as myelination. The PlpCreERT;Nf1fl/+ mice, a NF1 mouse model, have been demonstrated to exhibit structural aberrations in the BBB including malformations in the tight junctions among the endothelial cells, loss of gap junctions among astrocyte end-feet, and increased number and size of mitochondria in astrocytes signifying increased metabolism at the site, linking malformations in the structure of the BBB to functional abnormalities. Moreover, western blot analysis of optic nerve lysates showed increased nitric oxide synthase expression. We used this genetic model to assess the role of the BBB in neuropathology, such as NF1, and hypothesized that oligodendrocytes regulate the BBB. The results demonstrate that fibrin(ogen) and proinflammatory cells transmigrate into the parenchyma of the CNS of PlpCreERT;Nf1fl/+ mice. The humoral components found in the CNS disrupt the myelin encompassing the neurons as shown by electron micrographs. Moreover, hemotaxylin and eosin staining of the CNS revealed a wider corpus callosum in PlpCreERT;Nf1fl/+ mice compared to wild type mice. Consequently, the PlpCreERT;Nf1fl/+ mice exhibit deficits in pre-pulse inhibition startle responses and hyperactive movements. However, administrating a non-specific nitric oxide synthase inhibitor rescued the myelin decompaction. In addition, PlpCreERT;Nf1fl/+ and wild type mice revealed that pertussis toxin is not necessary for experimental autoimmune encephalomyelitis induction.
Jonathan Katz, Ph.D. (Committee Chair)
Richard Strait, M.D. (Committee Member)
Nancy Ratner, Ph.D. (Committee Member)
60 p.
Immunology

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Citations

  • Silbak, S. H. (2015). Insight into the Regulation of the Blood-Brain Barrier [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308364

    APA Style (7th edition)

  • Silbak, Sadiq. Insight into the Regulation of the Blood-Brain Barrier. 2015. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308364.

    MLA Style (8th edition)

  • Silbak, Sadiq. "Insight into the Regulation of the Blood-Brain Barrier." Master's thesis, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308364

    Chicago Manual of Style (17th edition)

ucin1439308364
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This open access ETD is published by University of Cincinnati and OhioLINK.