Simulation Study of Soluble Toxic Oligomeric Structures of Amyloid-Beta

Although early attention has focused on toxicity of amyloid plaques as the cause of Alzheimer's disease (AD), there is stronger evidence that soluble Aβ oligomers, and more recently pre-fibrillar oligomers, show better correlation with AD symptoms than do the insoluble fibrillar states exhibited at the completion of the amyloid cascade. In recent work a new oligomeric Aβ form known as the "globulomer" was found to inhibit calcium uptake by neuronal cells and to contribute to memory loss in lab animals. At present we have no knowledge of the globulomer structure, nor a smaller species known as the pre-globulomer, which is usually a necessary first step in the design of small molecule drug therapeutics. We will present our hypothesis about the structural ensembles of these two oligomeric forms based on molecular dynamics simulations and calculation of NMR observables and amide exchange data.