TY - JOUR
T1 - The peculiar role of the A2V mutation in amyloid-β (Aβ) 1-42 molecular assembly
AU - Messa, Massimo
AU - Colombo, Laura
AU - Del Favero, Elena
AU - Cantù, Laura
AU - Stoilova, Tatiana
AU - Cagnotto, Alfredo
AU - Rossi, Alessandro
AU - Morbin, Michela
AU - Di Fede, Giuseppe
AU - Tagliavini, Fabrizio
AU - Salmona, Mario
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84906871317&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906871317&partnerID=8YFLogxK
U2 - 10.1074/jbc.M114.576256
DO - 10.1074/jbc.M114.576256
M3 - Article
C2 - 25037228
AN - SCOPUS:84906871317
VL - 289
SP - 4143
EP - 24152
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 35
ER -