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

作者：Cantu Laura; Colombo Laura; Stoilova Tatiana; Deme Bruno; Inouye Hideyo; Booth Rachel; Rondelli Valeria; Di Fede Giuseppe; Tagliavini Fabrizio; Del Favero Elena; Kirschner Daniel A; Salmona Mario^*

来源：Scientific Reports, 2017, 7(1): 5510.

DOI：10.1038/s41598-017-05582-9

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-beta (A beta) 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 A beta peptides and their mixture. We have carried out neutron diffraction (ND) and x-ray diffraction (XRD) experiments on magnetically-oriented fibers of A beta 1-28WT and its variant A beta 1-28A2V. The orientation propensity was higher for A beta 1-28A2V suggesting that it promotes the formation of fibrillar assemblies. The diffraction patterns by A beta 1-28WT and A beta 128A2V 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 A beta 1-28WT and a short N-terminal fragment, A beta 1-6A2V, which supports a role of A beta' s N-terminal domain in amyloid fibril formation.

• 出版日期2017-7-14
• 单位东北大学