Affiliations: [a] Department of Pathology, The University of Melbourne Parkville, Victoria, Australia | [b] Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne Parkville, Victoria, Australia | [c] Mental Health Research Institute, The University of Melbourne Parkville, Victoria, Australia | [d] School of Physics, Monash University, Monash, Australia | [e] Centre for Neuroscience, The University of Melbourne Parkville, Victoria, Australia
Correspondence:
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Correspondence to: Kevin Barnham, Department of Pathology, The University of Melbourne, Victoria, 3010 Australia. Tel.: +61 3 83442555; Fax: +61 3 93476750; E-mail: [email protected].
Note: [1] Present address: Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.
Note: [] Handling Associate Editor: Brett Garner
Abstract: Amyloid-β peptide (Aβ) toxicity is thought to be responsible for the neurodegeneration associated with Alzheimer's disease. While the mechanism(s) that modulate this toxicity are still widely debated, it has previously been demonstrated that modifications to the three histidine residues (6, 13, and 14) of Aβ are able to modulate the toxicity. Therefore to further elucidate the potential role of the histidine (H) residues in Aβ toxicity, we synthesized Aβ peptides with single alanine substitutions for each of the three histidine residues and ascertained how these substitutions affect peptide aggregation, metal binding, redox chemistry, and cell membrane interactions, factors which have previously been shown to modulate Aβ toxicity. Aβ42 H13A and Aβ42 H6A modified peptides were able to induce significant cell toxicity in primary cortical cell cultures at levels similar to the wild-type peptide. However, Aβ42 H14A did not induce any measurable toxicity in the same cultures. This lack of toxicity correlated with the inability of the Aβ42 H14A to bind to cell membranes. The interaction of Aβ with cell membranes has previously been shown to be dependent on electrostatic interactions between Aβ and the negatively charged head group of phosphatidylserine. Our data suggests that it is the imidazole sidechain of histidine 14 that modulates this interaction and strategies inhibiting this interaction may have therapeutic potential for Alzheimer's disease.
