The peculiar role of the A2V mutation in amyloid-β (Aβ) 1-42 molecular assembly

Massimo Messa, Laura Colombo, Elena Del Favero, Laura Cantù, Tatiana Stoilova, Alfredo Cagnotto, Alessandro Rossi, Michela Morbin, Giuseppe Di Fede, Fabrizio Tagliavini, Mario Salmona

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We recently reported a novel Aβ precursor protein mutation (A673V), corresponding to position 2 of Aβ1-42 peptides (Aβ1-42A2V), that caused an early onset AD-type dementia in a homozygous individual. The heterozygous relatives were not affected as an indication of autosomal recessive inheritance of this mutation. We investigated the folding kinetics of native unfolded Aβ1-42A2V in comparison with the wild type sequence (Aβ1-42WT) and the equimolar solution of both peptides (Aβ1-42MIX) to characterize the oligomers that are produced in the early phases. We carried out the structural characterization of the three preparations using electron and atomic force microscopy, fluorescence emission, and x-ray diffraction and described the soluble oligomer formation kinetics by laser light scattering. The mutation promoted a peculiar pathway of oligomerization, forming a connected system similar to a polymer network with hydrophobic residues on the external surface. Aβ1-42MIX generated assemblies very similar to those produced by Aβ1-42WT, albeit with slower kinetics due to the difficulties of Aβ1-42WT and Aβ1-42A2V peptides in building up of stable intermolecular interaction.

Original languageEnglish
Pages (from-to)4143-24152
Number of pages20010
JournalJournal of Biological Chemistry
Issue number35
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Biochemistry
  • Medicine(all)


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