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Title page for ETD etd-12172018-113749


Type of Document Dissertation
Author Barton, Shawn Michael
Author's Email Address shawn.m.barton@vanderbilt.edu
URN etd-12172018-113749
Title Innovations in Delivery of Theranostic Agents Across Biological Barriers for Applications in Alzheimer’s Disease
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Manus Donahue Committee Chair
Douglas McMahon Committee Member
John Gore Committee Member
Wellington Pham Committee Member
Keywords
  • Alzheimers
  • amyloid
  • retina
  • 5XFAD
Date of Defense 2018-12-12
Availability restrictone
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss, language deficits, and executive dysfunction. Currently, there are no disease-modifying therapeutics available and major clinical trials have yielded no therapeutic benefits. Efforts to develop neurotherapeutics for AD and other neurologic disorders have been hindered by limited bioavailability due to the presence of the blood brain barrier (BBB). Previous attempts to target and clear amyloid beta (Aβ) plaques, a key pathologic mediator of AD, have had limited clinical success due to this biological barrier. To address this issue, we demonstrate in this work two distinct methods for improving delivery of theranostic agents to the brain. In one approach, using preclinical transgenic mouse models of AD, the BBB was breached in a condition amenable to acute inflammation, which allowed improved delivery of small and large materials to the brain parenchyma. Given the complexity of the biological and immunological events that emerge during inflammation, questions arise over the relative benefits and pernicious effects of this approach. Meanwhile, we demonstrated that aerosol administration also improves delivery to the brain without requiring BBB disruption, and thus may be more applicable to clinical translation.

From a developmental biology perspective, the retina is part of the central nervous system, functioning as a window to the brain from where the neuronal activity in the retina is transferred to the higher order visual processing brain regions via the optic nerve. Our hypothesis is that if Aβ deposits are present in the retina, they could serve as a surrogate biomarker for those in the brain and thus offers an opportunity for noninvasive Aβ imaging. Toward that approach, we are developing a method of retinal plaque detection using fluorescent Aβ-binding molecules that could be visualized using noninvasive retinal imaging. Such a test could be used to clinically evaluate retinal pathology as a predictive biomarker for future development of AD.

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