Author : Xiang Yu
Publisher :
Page : 258 pages
File Size : 32,39 MB
Release : 2012
Category : Alzheimer's disease
ISBN :
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, pathologically linked to the abnormal self-aggregation of amyloid peptides ([Amyloid-beta] and tau) into amyloid fibrils. Accumulating evidence supports the "toxic oligomer hypothesis" that small soluble amyloid oligomers (intermediate species), rather than monomers (initial species) and insoluble fibrils (final species), are major toxic species responsible for neuron dysfunction and death. However, due to the polymorphic and transit nature of amyloid oligomers, atomic structures of amyloid oligomers are not available to date, causing the difficulty in the fundamental understanding of the mechanisms of amyloid formation and toxicity and in the rational design of structural-based inhibitors to treat AD. In this dissertation, we develop a multiscale computational framework to (1) determine atomic structures of amyloid oligomers; (2) investigate the conformation, orientation, and aggregation of amyloid oligomers upon adsorption on biological and artificial surfaces; (3) probe binding and inhibitory ability of organic ligands to amyloid oligomers. Throughout this work, we for the first time determine a series of atomic structures of [Amyloid-beta] micelles (Chapter II), [Amyloid-beta] globulomers (Chapter III), and tau fibrillar-like oligomers (Chapter IV). These oligomers vary considerably in overall structural morphologies, reflecting a highly polymorphic nature of amyloid oligomers in a rugged energy landscape. We also study the effects of cholesterol level on the mutual structure, dynamics, and interaction of [Amyloid-beta] and lipid bilayer (Chapter V). Increased cholesterol level greatly enhances [Amyloid-beta] binding to the bilayer, which provides atomic-level explanation as to why high-level cholesterol may have a higher risk for AD development. In parallel to lipid bilayer, molecular dynamics simulations of [Amyloid-beta] peptides on graphite reveal the important role of hydrophobic interactions in facilitating [Amyloid-beta] adsorption, reorientation, structural transition, and aggregation (Chapter VI). With the assistance of atomic structures of [Amyloid-beta] oligomers, we computationally examine binding events between tanshinones and [Amyloid-beta] oligomer (Chapter VII). Strong binding affinity of tanshinone-I, rather tanshinone-IIA, to [Amyloid-beta] is well correlated with inhibitory activity to [Amyloid-beta] aggregation. Combination of our computational and experimental results represent an important step towards a better understanding of the aggregation, toxicity, and inhibition mechanisms of amyloid peptides at atomic level.