Date of Award
Open Access Dissertation
Epidemiology and Biostatistics
Melissa Ann Moss
Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. As the disease advances, symptoms include confusion, language skill breakdown, and long term memory loss - and culminate in death. Existing therapies for AD provide symptomatic benefits but cannot halt or slow the disease pathogenesis.
Increasing evidence reveals the multi-factorial nature of AD. Numerous factors, including amyloid-β (Aβ) aggregation, calcium homeostasis dysregulation, and oxidative stress, contribute to disease development and interplay with each other. Therefore, multi-target directed ligands (MTDLs) may present an effective AD treatment. Among all factors, Aβ aggregation is suggested to play the most crucial role. Compounds containing aromatic centers have been proposed as effective Aβ aggregation inhibitors; however, the influence of functional groups on the aromatic ring and the number of aromatic structures has not been comprehensively explored. Furthermore, the addition of functional groups presents an opportunity to endow therapeutic compounds with additional properties that can target other pathogenic pathways.
The work presented here examines three potential MTDLs for AD. First, experimentation investigates inhibitory capabilities of a group of FDA-approved calcium channel blockers, dihydropyridines, in Aβ aggregation. Results identify all selected dihydropyridines as inhibiters of Aβ aggregation that exhibit distinct mechanisms. These mechanistic differences alter the morphology of Aβ aggregates, which may be related to cytotoxicity. In addition, naphthalimide analogs were identified as novel inhibitors of Aβ aggregation. Several naphthalimide analogs with distinct lengths of the carbon linker were tested, and those with a two-carbon linker showed a significant inhibition by delaying the onset of aggregation. By introducing hydroxyl groups on the phenyl ring, the inhibitory capability of this compound was further enhanced and antioxidant activity was endowed. Finally, anthocyanidins, a group of polyphenols, were investigated for their ability to both intervene with Aβ aggregation and perform as antioxidants. Results indicate that anthocyanidins exhibit potent antioxidant activities, and inhibit the earlier stages of Aβ aggregation. Furthermore, the inhibitory capability is related to the number of hydroxyl groups. Together, this study provides insight into the effective properties of dihydropyridines, naphthalimides, and anthocyanidins as novel promising MTDLs for the pathogenesis in AD.
Tseng, J.(2014). Discovery and Characterization of Multi-Target Directed Ligands as Inhibitors of Amyloid-β Aggregation and Regulators of Alzheimer's Disease. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/2693