Histidine 14 modulates membrane binding and neurotoxicity of the alzheimer's disease amyloid-beta peptide

Danielle G Smith, Giuseppe D Ciccotosto, Deborah J Tew, Keyla Perez, Cyril C Curtain, John Frank Boas, Colin L Masters, Roberto Cappai, Kevin J Barnham

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    Abstract

    Amyloid-beta peptide (A beta) 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 A beta are able to modulate the toxicity. Therefore to further elucidate the potential role of the histidine (H) residues in A beta toxicity, we synthesized A beta 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 A beta toxicity. A beta(42) H13A and A beta(42) H6A modified peptides were able to induce significant cell toxicity in primary cortical cell cultures at levels similar to the wild-type peptide. However, A beta(42) H14A did not induce any measurable toxicity in the same cultures. This lack of toxicity correlated with the inability of the A beta(42) H14A to bind to cell membranes. The interaction of A beta with cell membranes has previously been shown to be dependent on electrostatic interactions between A beta 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.
    Original languageEnglish
    Pages (from-to)1387 - 1400
    Number of pages14
    JournalJournal of Alzheimer's Disease
    Volume19
    Issue number4
    DOIs
    Publication statusPublished - 2010

    Cite this

    Smith, D. G., Ciccotosto, G. D., Tew, D. J., Perez, K., Curtain, C. C., Boas, J. F., Masters, C. L., Cappai, R., & Barnham, K. J. (2010). Histidine 14 modulates membrane binding and neurotoxicity of the alzheimer's disease amyloid-beta peptide. Journal of Alzheimer's Disease, 19(4), 1387 - 1400. https://doi.org/10.3233/JAD-2010-1334