Two Disaccharides And Trimethylamine N-Oxide Affect A Beta Aggregation Differently, But All Attenuate Oligomer-Induced Membrane Permeability

Interaction between aggregates of amyloid beta protein (A beta) and membranes has been hypothesized by many to be a key event in the mechanism of neurotoxicity associated with Alzheimer's disease (AD). Proposed membrane-related mechanisms of neurotoxicity include ion channel formation, membrane disruption, changes in membrane capacitance, and lipid membrane oxidation. Recently, osmolytes such its trehalose have been found to delay A beta aggregation in vitro and reduce neurotoxicity. However, no direct measurements have separated the effects of osmolytes on A beta aggregation versus membrane interactions. In this article, we tested the influence of trehalose, sucrose and trimethylamine-N-oxide (TMAO) on A beta aggregation and fluorescent dye leakage induced by A beta aggregates from liposomes. In the absence of lipid vesicles, trehalose and sucrose, but not TMAO, were found to delay A beta aggregation. In contrast, all of the osmolytes significantly attenuated dye leakage. Dissolution of preformed A beta aggregates was excluded as it possible mechanism of dye leakage attenuation by measurements of Congo red binding as well as hydrogen-deuterium exchange detected by mass spectrometry (HX-MS). However, the accelerated conversion of high order oligomers to fibril caused by vesicles did not take place if any of the three osmolytes presented. Instead, in the case of disaccharide, osmolytes were found to form adducts with A beta, and change the dissociation dynamics of soluble oligomeric species. Both effects may have contributed to the observed osmolyte attenuation of dye leakage. These results suggest that disaccharides and TMAO may have very different effects on A beta aggregation because of the different tendencies of the osmolytes to interact with the peptide backbone. However, the effects on A beta membrane interaction may be due to much more general phenomena associated with osmolyte enhancement of A beta oligomer stability and/or direct interaction of osmolyte with the membrane surface.