| Alzheimers Disease (AD) is the most commonly diagnosed cause of progressive dementia in the 65 and over age group. No currently approved, or experimental, drug has been shown to have a disease modifying effect in human AD. Hypotheses on the etiology of AD have revolved around the excessive production of beta amyloid, resulting in amyloid plaques, or tau, resulting in neurofibrillary tangles. Recent experiments with transgenic animal models of AD suggest that soluble oligomers of beta amyloid initiate a series of events, including increase in soluble tau, that result in neuronal dysfunction and death. However the major known risk factors for late onset AD in humans are associated with vascular dysfunction. A new hypothesis, known as ABSENT, factors the combined effects of beta amyloid on neurons and the vascular system. The hypothesis, as outlined in Chapter 2, creates a biologically unified and chemically feasible framework for integrating our current understanding of the various facets of AD. The use of computer assisted drug design can speed up the process of drug discovery, however the flexible nature of beta amyloid and peptidic ligands that block its oligomerization necessitate development of new techniques (and protocols) to handle such atypical receptor-ligand systems. Chapter 3 describes the creation of a beta amyloid receptor model, as well as techniques and protocols to dock peptidic ligands. The results demonstrate that it is possible to model experimentally derived structure activity relationships, and is the basis for the design of novel classes of ligands as described in Chapter 4. Four classes, based on the chirality of residues and predicted mode of binding are also explored in that chapter. Initial synthesis and basic experimental characterization of a few novel ligands are described in Chapter 5. The results of Thioflavin T and Western Blot assays show that the new ligands are superior to existing ligands at blocking beta amyloid fibrillization and oligomerization. Circular Dichroism is also used to demonstrate binding of the ligands to beta amyloid. Chapter 6 describes future experiments for more thorough characterization of novel designed ligands. |
