title: Single-molecule imaging reveals aβ42:aβ40 ratio-dependent oligomer growth on neuronal processes.
abstract: Soluble oligomers of the amyloid-β peptide have been implicated as proximal neurotoxins in Alzheimer's disease. However, the identity of the neurotoxic aggregate(s) and the mechanisms by which these species induce neuronal dysfunction remain uncertain. Physiologically relevant experimentation is hindered by the low endogenous concentrations of the peptide, the metastability of Aβ oligomers, and the wide range of observed interactions between Aβ and biological membranes. Single-molecule microscopy represents one avenue for overcoming these challenges. Using this technique, we find that Aβ binds to primary rat hippocampal neurons at physiological concentrations. Although amyloid-β(1-40) as well as amyloid-β(1-42) initially form larger oligomers on neurites than on glass slides, a 1:1 mix of the two peptides result in smaller neurite-bound oligomers than those detected on-slide or for either peptide alone. With 1 nM peptide in solution, Aβ40 oligomers do not grow over the course of 48 h, Aβ42 oligomers grow slightly, and oligomers of a 1:1 mix grow substantially. Evidently, small Aβ oligomers are capable of binding to neurons at physiological concentrations and grow at rates dependent on local Aβ42:Aβ40 ratios. These results are intriguing in light of the increased Aβ42:Aβ40 ratios shown to correlate with familial Alzheimer's disease mutations.
authors: Department of Biophysics, University of Michigan, Ann Arbor, MI, USA. johnsoro@umich.edu
authors: Robin D
authors: RD
authors: Johnson
authors: Joseph A
authors: JA
authors: Schauerte
authors: Chun-Chieh
authors: CC
authors: Chang
authors: Kathleen C
authors: KC
authors: Wisser
authors: John Christian
authors: JC
authors: Althaus
authors: Cynthia J L
authors: CJ
authors: Carruthers
authors: Michael A
authors: MA
authors: Sutton
authors: Duncan G
authors: DG
authors: Steel
authors: Ari
authors: A
authors: Gafni
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D007425:Intracellular Membranes / Q000737:chemistry / Q000378:metabolism; D008856:Microscopy, Fluorescence; D016501:Neurites / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization; D021122:Protein Subunits; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D021122:Protein Subunits; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)