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Expediting the Discovery and Potential Translation of Theranostic Agents for Alzheimer's Disease

dc.creatorMcClure, Richard Anthony
dc.description.abstractAlzheimer'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.
dc.titleExpediting the Discovery and Potential Translation of Theranostic Agents for Alzheimer's Disease
dc.contributor.committeeMemberWellington Pham
dc.contributor.committeeMemberDanny Winder
dc.contributor.committeeMemberJohn C Gore
dc.contributor.committeeMemberManus Donahue
dc.type.materialtext University

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