title: The peculiar role of the A2V mutation in amyloid-β (Aβ) 1-42 molecular assembly.
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.
authors.affiliation: From the Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Messa
authors.affiliation: From the Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, V.le F.lli Cervi 93, 20090 Segrate, Italy, and.
authors.forename: Elena
authors.initials: E
authors.lastname: del Favero
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, V.le F.lli Cervi 93, 20090 Segrate, Italy, and.
authors.forename: Laura
authors.initials: L
authors.lastname: Cantù
authors.affiliation: From the Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Stoilova
authors.affiliation: From the Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.affiliation: From the Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Neurology V and Neuropathology, IRCCS Foundation "Carlo Besta" Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.affiliation: Neurology V and Neuropathology, IRCCS Foundation "Carlo Besta" Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Fede
authors.affiliation: Neurology V and Neuropathology, IRCCS Foundation "Carlo Besta" Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: From the Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy, mario.salmona@marionegri.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics*; D002942:Circular Dichroism; D006801:Humans; D007700:Kinetics; D018625:Microscopy, Atomic Force; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics*; D058105:Polymerization; D017510:Protein Folding; D053838:Scattering, Small Angle; D013050:Spectrometry, Fluorescence; D014961:X-Ray Diffraction
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer Disease; Amyloid; Amyloid Precursor Protein (APP); Amyloid-β (Aβ); Protein Aggregation