| Research Interest β amyloid peptide (Aβ) is believed to play a key role in the mechanism of Alzheimer’s disease (AD). Aβ tends to associate and form amyloid fibrillar aggregates rich in β-sheet content. A variety of evidence indicates that Aβ aggregates are toxic in vitro, and the presence of certain Aβ oligomers species appear to be correlated with AD pathology in vivo. An early ‘Aβ hypothesis’ postulated that AD was the consequence of neuron death induced by insoluble deposits of large Aβ fibrils. However, newer findings indicate that the small soluble Aβ intermediate oligomers are more neurotoxic than the fibrils. Yet, the structure of the toxic Aβ species and the pathway by which it forms are unknown. Our experimental data imply that the toxic intermediate and fibril share the same molecular level structure, suggesting that the intermediate is a small structural unit similar to the fibril. This result may imply that the intermediate appears more toxic than the fibril due to its higher mobility and higher concentration, and not due to differences in structure specific interactions of the different aggregated species. We developed a simplified model, which can explain the differences in biological activity between the toxic intermediate and the mature fibrils, using a diffusion-limited reaction model and geometry considerations. In the light of our hypothesis that the toxic intermediate and fibril share the same molecular level structure, we are currently studying the interaction of Aβ fibrils with known inhibitors of aggregation or toxicity. There is only limited understanding of how such inhibitors interact with Aβ, and specifically the locations of the binding sites of these inhibitors on the Aβ fibril or intermediate are unknown. We are using docking to predict those interactions and elucidate inhibitors binding sites. We hypothesis that different toxicity inhibitors will share some of the binding sites, and that the shared binding sites will play a significant role in the interactions associated with toxicity. Presently, we have identified several reoccurring binding sites among the toxicity inhibitors tested. Our findings will be then tested experimentally by using chemically modified Aβ or Aβ mutants with amino acid substitutions at the suspected binding sites. |