| Alzheimer's disease (AD) is the most common form of dementia. AD fatalities are constantly increasing, so are the financial costs associated with the disease. Despite significant scientific advancements during the last 20 years in understanding the disease, there are still no approved drugs available that slow or reverse AD progression. AD is thought be initiated by the accumulation of the beta-Amyloid (Abeta) peptide in the brain, which aggregates extracellularly to form neurotoxic species. Abeta eventually forms insoluble fibrillar senile plaque, though certain forms of soluble aggregated oligomers are believed to be more toxic. One of the main barriers to curing AD is the lack of understanding of Abeta toxicity. Two critical issues in elucidating mechanism of Abeta toxicity are identifying the cellular damage induced by Abeta, and elucidating the surfaces or amino acids of Abeta that are key for the interaction with cells.;In the work presented in this dissertation we attempted to answer the latter, and contributed new information to our molecular understanding of Abeta neurotoxicity. We have identified differences in the structure of Arg5 between Abeta fibrils and the toxic oligomers. This is one of only a few molecular differences identified so far between the less toxic fibrils and the highly toxic oligomers, thus we suggest that this region may be important for Abeta biological activity. We then showed that alterations of Abeta around Arg5 change the propensity of Abeta to bind to cells. In the following chapter, using a simplified diffusion-limited reaction model for the interaction of Abeta with cells, we demonstrated that differences in the toxicity of Abeta aggregates with different sizes can be explained, at least partially, based on the diffusivity and concentration of species. We then used a combination of computational and experimental tools, to elucidate the Abeta binding sites of known toxicity inhibitors as a means to indirectly identify loci on Abeta aggregates that may be important for Abeta neurotoxicity. Our data indicates that despite their structural differences, the inhibitors bind at two common loci on Abeta, near Lys28 and near the C-terminus. We then explored the possible role of Lys28 in Abeta cell binding. We also launched a structure-based virtual screening to discover novel small molecular weight inhibitors that can bind at the two loci identified, and potentially inhibit Abeta biological activity. The results of our work provide new information that contributes to our understanding of Abeta neurotoxicity, and provides a foundation for the development of novel therapies for AD. |
