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-Î² (AÎ²) 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 AÎ² peptides and their mixture. We have carried out neutron diffraction (ND) and x-ray diffraction (XRD) experiments on magnetically-oriented fibers of AÎ²1-28WT and its variant AÎ²1-28A2V. The orientation propensity was higher for AÎ²1-28A2V suggesting that it promotes the formation of fibrillar assemblies. The diffraction patterns by AÎ²1-28WT and AÎ²1-28A2V 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 AÎ²1-28WT and a short N-terminal fragment, AÎ²1-6A2V, which supports a role of AÎ²'s N-terminal domain in amyloid fibril formation.
|Titolo:||The A2V mutation as a new tool for hindering AÎ² aggregation: A neutron and x-ray diffraction study|
|Settore Scientifico Disciplinare:||Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)|
|Data di pubblicazione:||2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/s41598-017-05582-9|
|Appare nelle tipologie:||01 - Articolo su periodico|