Date of Award
Campus Access Dissertation
Melissa A Moss
Alzheimer's disease (AD) is a neurodegenerative disease and is the most common type of dementia. In the U.S., AD is the one of the leading causes of death and is the third most costly disease. Current therapies for AD mainly focus on symptomatic treatment, which delays the onset of AD by enhancing neuron transmission signals. However, these therapies are not potentially disease-modifying and cannot cease the progression of this disease. The deposition of amyloid plaques in AD brains exhibits a causative link with this disease. Amyloid plaques are primarily comprised of aggregates formed by the amyloid- β proteins (A β). Inhibition of the formation of Aβ aggregates or disrupting pre-formed Aβ aggregates is widely considered to be a promising disease-modifying therapy.
In this study, a group of polyphenols, including flavone, apigenin, luteolin, 3'4'-dihydroxyflavone and 5,7,3'4'5'-pentahydroxyflavone, was investigated for their ability to disrupt Aβ fibrils. Results indicate that these polyphenols do not disassociate Aβ fibrils but interrupt Aβ fibrils-ThT interactions by completely or partially noncompetitive binding Aβ fibrils. By binding the aggregated Aβ, but not monomeric protein, 3'4'-dihydroxyflavone and 5,7,3'4'5'-pentahydroxyflavone are both effective inhibitors of Aβ aggregate lateral association but fail to inhibit aggregate elongation via monomer addition.
Based on a novel naphthalimide analog acetylcholinesterase inhibitior (AChEI), G-II-19, synthesized by Jie Gao in Dr. Chapman's laboratory, a group of naphthalimide analogs was synthesized as potential dual-function inhibitors for AChE and Aβ aggregation. Results identify several naphthalimide analogs as novel, effective inhibitors of Aβ aggregation. Two aromatic anchor groups are important for reducing the extent of Aβ aggregation. In contrast, the (dimethylamino)methyl-furan functionalization might interact with Aβ monomer or small oligomers to extend lag time, and this interaction might be enhanced by thiazole replacement.
Suo, C.(2011). Study of Polyphenols and Naphthalimide Analogs As Inhibitors of Amyloid- β Protein Aggregation In Alzheimer'S Disease. (Doctoral dissertation). Retrieved from http://scholarcommons.sc.edu/etd/536