In vitro monitoring of amyloid β-peptide oligomerization by Electrospray differential mobility analysis: An alternative tool to evaluate Alzheimer's disease drug candidates.
Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein aggregation, like more than twenty other human pathologies. One major protein incriminated in AD is the 42-residue amyloid-β peptide (Aβ1-42) which aggregates to form neurotoxic oligomers and fibrils. While, low molecular weight oligomers have been evidenced as neurotoxic species, only scarce methods raise the challenge to monitor the beginning of the aggregation process, called oligomerization. We propose here an innovative and fast monitoring of the time-dependent Aβ1-42oligomerization pattern by electrospray differential mobility analysis (ES-DMA). We developed a non-denaturing method based on ES-DMA to afford a real-time and direct characterization of the early, metastable and neurotoxic species. This technique provided their size distribution over time. At the beginning of the in vitro oligomerization process of Aβ1-42, the size distribution is characterized by two populations with modal diameters around 3.5 and 4nm, corresponding to Monomer and Small oligomers. After few hours, larger species around 10nm are observed. The results were correlated to those obtained by capillary electrophoresis. We also demonstrated the ability of our method to evaluate Aβ1-42kinetics modulators. Thereby, ES-DMA provides new insights on Aβ1-42oligomerization in the presence of sugar-based peptidomimetic analogs which were recently described as modulators of Aβ1-42self-assembly and neurotoxicity inhibitors.
Molécules Fluorées et Chimie Médicinale, BioCIS UMR 8076, Univ. Paris-Sud, CNRS, Université Paris Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France; Proteins and Nanotechnologies in Analytical Science, Institut Galien de Paris Sud, UMR 8612, Univ. Paris-Sud, CNRS, Université Paris Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
Dimitri
D
Brinet
Laboratoire National de Métrologie et d'Essais, LNE, Chemistry and Biology Division, 1 Rue Gaston Boissier, 75724 Paris Cedex 15, France.
François
F
Gaie-Levrel
Laboratoire National de Métrologie et d'Essais, LNE, Chemistry and Biology Division, 1 Rue Gaston Boissier, 75724 Paris Cedex 15, France.
Vincent
V
Delatour
Molécules Fluorées et Chimie Médicinale, BioCIS UMR 8076, Univ. Paris-Sud, CNRS, Université Paris Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
Julia
J
Kaffy
Molécules Fluorées et Chimie Médicinale, BioCIS UMR 8076, Univ. Paris-Sud, CNRS, Université Paris Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
Sandrine
S
Ongeri
Proteins and Nanotechnologies in Analytical Science, Institut Galien de Paris Sud, UMR 8612, Univ. Paris-Sud, CNRS, Université Paris Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France. Electronic address: myriam.taverna@u-psud.fr.
Myriam
M
Taverna
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000737:chemistry*; D016903:Drug Monitoring / Q000379:methods*; D019075:Electrophoresis, Capillary / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D000075663:Ion Mobility Spectrometry / Q000379:methods*; D007700:Kinetics
D016229:Amyloid beta-Peptides
Alzheimer's disease; Amyloid β-peptide aggregation; Capillary electrophoresis; Electrospray differential mobility analysis; Glycopeptides; Peptidomimetics