The A2V mutation as a new tool for hindering Aβ aggregation: A neutron and x-ray diffraction study

Laura Cantu', Laura Colombo, Tatiana Stoilova, Bruno Demé, Hideyo Inouye, Rachel Booth, Valeria Rondelli, Giuseppe Di Fede, Fabrizio Tagliavini, Elena Del Favero, Daniel A Kirschner, Mario Salmona

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We have described a novel C-to-T mutation in the APP gene that corresponds to an alanine to valine substitution at position 673 in APP (A673V), or position 2 of the amyloid-β (Aβ) sequence. This mutation is associated with the early onset of AD-type dementia in homozygous individuals, whereas it has a protective effect in the heterozygous state. Correspondingly, we observed differences in the aggregation properties of the wild-type and mutated Aβ peptides and their mixture. We have carried out neutron diffraction (ND) and x-ray diffraction (XRD) experiments on magnetically-oriented fibers of Aβ1-28WT and its variant Aβ1-28A2V. The orientation propensity was higher for Aβ1-28A2V suggesting that it promotes the formation of fibrillar assemblies. The diffraction patterns by Aβ1-28WT and Aβ1-28A2V assemblies differed in shape and position of the equatorial reflections, suggesting that the two peptides adopt distinct lateral packing of the diffracting units. The diffraction patterns from a mixture of the two peptides differed from those of the single components, indicating the presence of structural interference during assembly and orientation. The lowest orientation propensity was observed for a mixture of Aβ1-28WT and a short N-terminal fragment, Aβ1-6A2V, which supports a role of Aβ's N-terminal domain in amyloid fibril formation.

Original languageEnglish
Pages (from-to)5510
JournalScientific Reports
Issue number1
Publication statusPublished - Jul 14 2017


  • Journal Article


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