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

Wang, Qiuming
http://rave.ohiolink.edu/etdc/view?acc_num=akron1370282744

Abstract Details

2013, Doctor of Philosophy, University of Akron, Chemical Engineering.
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, conformation, and orientation of Aβ oligomer on Aβ-surface interaction (Chapter III and Chapter IV). As compared to Aβ aggregation in solution, all of the Self-Assembled Monolayers (SAMs) can greatly accelerate Aβ aggregation and promote the structural conversion from an unstructured conformation to a β-sheet-containing structure. Our results suggest that Aβ undergoes different aggregation pathways on different SAMs. All these experimental and simulation results represent the first important step towards a better fundamental understanding of amyloid aggregation and toxicity mechanisms at the molecular level. We also discover a type of novel inhibitors of tanshionones from herb extracts which possess multifunction of inhibiting Aβ aggregation, disaggregating Aβ fibers, and reducing Aβ-induced cell toxicity in vitro (Chapter V). Tanshinone-derived compounds constitute a new class of amyloid inhibitors with multiple advantages in amyloid inhibition, fibril disruption, and cell protection, as well as their well-known anti-inflammatory activity, which may hold great promise in treating amyloid diseases. In addition of investigating the naturally existed compounds, a novel technique for the design and identification of amyloidogenic hexapeptide-based Aβ inhibitor was developed (Chapter VI). We have suggested a novel hypothesis for the development of hexapeptide-based Aβ inhibitors and developed a high-throughput protocol for the design and screen of amyloidogenic hexapeptide sequences as Aβ aggregation and cytotoxicity inhibitors. The successful identification of Aβ inhibitors through this work highly confirmed that analyzing the self-recognition short peptide fragments is a promising strategy for developing peptide-based inhibitors of Alzheimer’s disease. And the common concept of cross-amylid interaction could also potentially be used to the identification of inhibitors for other amyloid diseases. The self-recognition hexapeptide fragments designed in QSAR model, in together with the high throughput MD simulation model, can be widely used for amyloidosis mechanism study and amyloid inhibitor screen.
Jie Zheng, Dr. (Advisor)
Gang Cheng, Dr. (Committee Member)
Steven Chuang, Dr. (Committee Member)
Bi-min Zhang Newby, Dr. (Committee Member)
Ge Zhang, Dr. (Committee Member)
214 p.
Chemical Engineering
Alzheimer Disease; Beta-Amyloid peptide Abeta; Structure; Aggregation; Inhibition; Self-Assembled Monolayers SAMs; AFM; SPR; QSAR; MD simulation; Drug Design

Recommended Citations

Citations

  • Wang, Q. (2013). Structure, Aggregation, and Inhibition of Alzheimer's B-Amyloid Peptide [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1370282744

    APA Style (7th edition)

  • Wang, Qiuming. Structure, Aggregation, and Inhibition of Alzheimer's B-Amyloid Peptide. 2013. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1370282744.

    MLA Style (8th edition)

  • Wang, Qiuming. "Structure, Aggregation, and Inhibition of Alzheimer's B-Amyloid Peptide." Doctoral dissertation, University of Akron, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=akron1370282744

    Chicago Manual of Style (17th edition)

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© 2013, all rights reserved.
This open access ETD is published by University of Akron and OhioLINK.