STABILIZATION OF NEUROTOXIC SOLUBLE -SHEET-RICH CONFORMATIONS OF THE ALZHEIMER'S DISEASE AMYLOID- PEPTIDE

¹ University of Melbourne
² Monash University
³ Leeds University
⁴ Walter and Eliza Hall Institute of Medical Research

^* To whom correspondence should be addressed. E-mail: kbarnham{at}unimelb.edu.au.

Submitted on August 15, 2007
Revised on October 9, 2007
Accepted on 1 November 2007

	Abstract

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- peptide (A) as the potential toxic species. Using a variety of methods we have analyzed how SDS modulates the folding of A40 and 42 and found that sub-micellar concentrations of SDS solubilize A and induce structural transitions. Under these conditions A40 and 42 are interconverting oligomeric ensembles with a predominantly -sheet structure. The A42 soluble oligomers form -sheet structures more readily and have increased stability compared with A40 under identical conditions. The presence of added Cu²⁺ significantly promotes and stabilizes the formation of the soluble oligomeric -sheet structures but these structures are "non-amyloidogenic". In contrast, in the absence of added Cu²⁺ these -sheet oligomers possess the hallmarks of "amyloidogenic" structures. These SDS induced -sheet forms of A, both in the presence and absence of Cu²⁺, are toxic to neuronal cells.

Key Words: Alzheimer's disease, amyloid beta, soluble oligomers, structural transitions, submicellar SDS