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

July 14, 2017
Laura Cantu, Laura Colombo, Tatiana Stoilova, Bruno Deme, Hideyo Inouye, Rachel Booth, Valeria Rondelli, Giuiseppe Di Fede, Fabrizio Tagliavini, Elena Del Favero, Daniel A. Kirschner & Mario Salmona
Scientific Reports

Abstract
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.
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