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, 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-beta peptide (Abeta) as the potential toxic species. Using a variety of methods, we have analyzed how sodium dodecyl sulphate (SDS) modulates the folding of Abeta40 and 42 and found that submicellar 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 nonamyloidogenic. 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.
Tew
Deborah J
DJ
Department of Pathology, Centre for Neuroscience, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
Bottomley
Stephen P
SP
Smith
David P
DP
Ciccotosto
Giuseppe D
GD
Babon
Jeffrey
J
Hinds
Mark G
MG
Masters
Colin L
CL
Cappai
Roberto
R
Barnham
Kevin J
KJ
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology / Q000648:ultrastructure*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D009498:Neurotoxins / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D009498:Neurotoxins