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

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.