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.

The Peculiar role of the A2V mutation in amyloid-β (Aβ) 1-42 molecular assembly / M. Messa, L. Colombo, E. Del Favero, L. Cantù, T. Stoilova, A. Cagnotto, A. Rossi, M. Morbin, G. Di Fede, F. Tagliavini, M. Salmona. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 289:35(2014 Aug 29), pp. 24143-24152.

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

M. Messa;E. Del Favero;L. Cantù;
2014

Abstract

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.
Alzheimer disease ; amyloid ; amyloid precursor protein (APP) ; amyloid-β (Aβ) ; protein aggregation
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
29-ago-2014
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/238892
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