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Title page for ETD etd-08212015-140759


Type of Document Dissertation
Author McClure, Richard Anthony
Author's Email Address mcclurra@gmail.com
URN etd-08212015-140759
Title Expediting the Discovery and Potential Translation of Theranostic Agents for Alzheimer's Disease
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Danny Winder Committee Member
John C Gore Committee Member
Manus Donahue Committee Member
Wellington Pham Committee Member
Keywords
  • Imaging
  • High-throughput
  • Nebulization
  • Alzheimers
  • Amyloid
  • Aerosol
  • Curcumin
Date of Defense 2015-07-21
Availability unrestricted
Abstract
Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder characterized by a progressive and inexorable loss of cognitive function most likely attributable to the accumulation of amyloid-β (Aβ) peptide in the brain. Despite this unique molecular etiology, due to the phenotypic homogeneity of neurological disorders included in the differential diagnosis of cognitive impairment, accurately distinguishing AD from non-amyloid-β (Aβ) causes of dementia continues to represent a significant bottleneck in AD research. Notably, the identification of amyloid-binding compounds is a crucial step in the development of imaging probes which can overcome this limitation. Moreover, assuming that amyloid-centric hypotheses are correct, then preventing Aβ plaque formation or facilitating their demolition, particularly during the early disease process, represents a key therapeutic strategy. Disappointingly, the clinical impact of Aβ-binding molecules has been historically stunted due to a systemic underestimation of the impenetrable nature of the blood brain barrier (BBB). Here, with the intent of expanding the chemical genetics of amyloid-binding molecules via the repurposing of hit compounds as theranostic agents for AD, we integrate a novel fluorescence assay with imaging mass spectrometry to screen existing molecular libraries for precursor structures with the ability to both cross the BBB and bind to Aβ-plaques. The therapeutic efficacy of the lead compound identified via this two-phase screening approach, promethazine, was then demonstrated in a preclinical mouse model of AD. In addition, we hypothesized that atomizer technology could be leveraged to enhance the bioavailability of existing disease-modifying therapeutics for AD. In this work, we successfully recapitulated the therapeutic efficacy achieved via intravenous administration of curcumin, but in a dosing regimen compatible with clinical implementation. Together, it is our hope that these scientific contributions will advance the field towards the clinical implementation of the first disease-modifying therapeutic for AD.

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