Single-Molecule Imaging Reveals Aβ42:Aβ40 Ratio-Dependent Oligomer Growth on Neuronal Processes

Soluble oligomers of the amyloid-beta 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 A beta oligomers, and the wide range of observed interactions between A beta and biological membranes. Single-molecule microscopy represents one avenue for overcoming these challenges. Using this technique, we find that A beta binds to primary rat hippocampal neurons at physiological concentrations. Although amyloid-beta(1-40) as well as amyloid-beta(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, A beta 40 oligomers do not grow over the course of 48 h, A beta 42 oligomers grow slightly, and oligomers of a 1:1 mix grow substantially. Evidently, small A beta oligomers are capable of binding to neurons at physiological concentrations and grow at rates dependent on local A beta 42:A beta 40 ratios. These results are intriguing in light of the increased A beta 42:A beta 40 ratios shown to correlate with familial Alzheimer's disease mutations.