The Peculiar Role of the A2V Mutation in Amyloid-β (Aβ) 1–42 Molecular Assembly

• Published in: The Journal of biological chemistry 2014-08, Vol.289 (35), p.24143-24152
• Main Authors: Messa, Massimo, Colombo, Laura, del Favero, Elena, Cantù, Laura, Stoilova, Tatiana, Cagnotto, Alfredo, Rossi, Alessandro, Morbin, Michela, Di Fede, Giuseppe, Tagliavini, Fabrizio, Salmona, Mario
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Circular Dichroism; Humans; Kinetics; Microscopy, Atomic Force; Mutation; Peptide Fragments - chemistry; Peptide Fragments - genetics; Polymerization; Protein Folding; Protein Structure and Folding; Scattering, Small Angle; Spectrometry, Fluorescence; X-Ray Diffraction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.576256

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.