Polymorphism in alzheimer Aβ amyloid organization reflects conformational selection in a rugged energy landscape

Experimental and computational studies of Aβ amyloids have suggested that for any given segment there are one or more preferred parallel and (or) antiparallel structural states. The preferred organizations of the Aβ fragments do not appear to present straight forward rules with respect to length, hydrophobicity, and charge. Because polymorphism is presented by different Aβ segments, clearly a combination of these segments would lead to polymorphic full-length Aβ, although the relative populations in the full sequence are likely to be different. How the Aβ peptides assemble and form toxic entities and what is the mechanism of toxicity are major questions that persist in Alzheimer research. Two types of models of the three-dimensional structures of Aβ oligomers have been reported from computational and experimental studies. Because metal ions can coordinate with different residues in each structural model, the variety of the morphologies can increase quickly.