Structure, Aggregation, and Inhibition of Alzheimer's B-Amyloid Peptide

Alzheimer's disease (AD) is the most common age related neurodegenerative disorder pathologically linked with the accumulation of the extracellular senile plaques of β-Amyloid peptide (Aβ) and the intracellular neurofibrillary tangles of tau protein in AD's brains.The deposition of Aβ is regarded as the primary causative factor in AD, which involves both neuron cytotoxicity and tau protein hydrophosphorylation. Amyloid formation on the cell membrane involves multiple self-assembly processes in which Aβ peptides undergo complex conformational change, aggregation, and reorganization to form characteristic β-sheet rich fibrils.The kinetics of this self-assembly process and the inhibition of Aβ aggregation and toxicity remains an important but open question because of 1) the small size, fast transition, and heterogeneous intermediates of Aβ oligomers, 2) complicated surface environment of cell membrane, and 3) no effective pharmaceutical agent was produced to date to treat AD.In this dissertation, both computational and experimental approaches were conducted to ( 1) investigate the conformation, orientation, and aggregation of amyloid oligomers upon adsorption on artificial surfaces; (2) determine seeding effect of Aβ adsorption and kinetic on different artificial surfaces; (3) examine inhibition effect of tanshiones on Aβ aggregation and toxicity; (4) explore novel process for Aβ inhibitor design.Throughout this week, we for the first time determine the effect of surface chemistry on Aβ aggregation and adsorption (Chapter II); and reveal the role of size, Zheng for persevering with me as my advisor though out the time it took me to complete this research and write the dissertation.Dr. Jie Zheng has been a wonderful mentor, colleague