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

Deborah J. Tew ^*  ¶, Stephen P. Bottomley , David P. Smith ^* ¶, Giuseppe D. Ciccotosto ^*  ¶, Jeffrey Babon ^||, Mark G. Hinds ^||, Colin L. Masters  ^¶, Roberto Cappai ^*   ¶ and Kevin J. Barnham ^*  ¶

^* Department of Pathology, Centre for Neuroscience, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia; ^¶ The Mental Health Research Institute of Victoria, Parkville, Victoria, Australia; Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia; and ^|| Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Correspondence: Address reprint requests to Kevin J. Barnham, E-mail: kbarnham{at}unimelb.edu.au.

An emerging paradigm for degenerative diseases associated with protein misfolding, such as Alzheimer's disease, is the formation of a toxic species due to structural transitions accompanied by oligomerization. Increasingly, the focus in Alzheimer's disease is on soluble oligomeric forms of the amyloid-β peptide (Aβ) as the potential toxic species. Using a variety of methods, we have analyzed how sodium dodecyl sulphate (SDS) modulates the folding of Aβ40 and 42 and found that submicellar concentrations of SDS solubilize Aβ and induce structural transitions. Under these conditions, Aβ40 and 42 are interconverting oligomeric ensembles with a predominantly β-sheet structure. The Aβ42 soluble oligomers form β-sheet structures more readily and have increased stability compared with Aβ40 under identical conditions. The presence of added Cu²⁺ significantly promotes and stabilizes the formation of the soluble oligomeric β-sheet structures but these structures are nonamyloidogenic. In contrast, in the absence of added Cu²⁺, these β-sheet oligomers possess the hallmarks of amyloidogenic structures. These SDS-induced β-sheet forms of Aβ, both in the presence and absence of Cu²⁺, are toxic to neuronal cells.