Stabilization of Neurotoxic Soluble beta-Sheet-Rich Conformations of the Alzheimer's Disease Amyloid-beta Peptide

An emerging paradigm for degenerative diseases associated with protein misfolding, such as Alzheimer s disease (AD)(1), is the formation of a toxic species due to structural transitions accompanied by oligomerisation. Increasingly, the focus in Alzheimer s disease is on soluble oligomeric forms of the amyloid-beta peptide (Abeta) as the potential toxic species. Using a variety of methods we have analyzed how SDS modulates the folding of Abeta40 and 42 and found that sub-micellar concentrations of SDS solubilize Abeta and induce structural transitions. Under these conditions Abeta40 and 42 are interconverting oligomeric ensembles with a predominantly beta-sheet structure. The Abeta42 soluble oligomers form beta-sheet structures more readily and have increased stability compared with Abeta40 under identical conditions. The presence of added Cu(2+) significantly promotes and stabilizes the formation of the soluble oligomeric beta-sheet structures but these structures are non-amyloidogenic . In contrast, in the absence of added Cu(2+) these beta-sheet oligomers possess the hallmarks of amyloidogenic structures. These SDS induced beta-sheet forms of Abeta, both in the presence and absence of Cu(2+), are toxic to neuronal cells.