There is an ongoing debate regarding the culprits of cytotoxicity associated with amyloid disorders. Although small pre-fibrillar amyloid oligomers have been implicated as the pri-mary toxic species, the fibrillar amyloid material itself can also induce cytotoxicity. To inves-tigate membrane disruption and cytotoxic effects associated with intact and fragmented fibrils, the novel in situ spectroscopic technique of Total Internal Reflection Ellipsometry (TIRE) was used. Fibril lipid interactions were monitored using natively derived whole cell membranes as a model of the in vivo environment. We show that fragmented fibrils have an increased ability to disrupt these natively derived membranes by causing a loss of material from the deposited surface when compared with unfragmented fibrils. This effect was cor-roborated by observations of membrane disruption in live cells, and by dye release assay using synthetic liposomes. Through these studies we demonstrate the use of TIRE for the analysis of protein-lipid interactions on natively derived lipid surfaces, and provide an expla-nation on how amyloid fibrils can cause a toxic gain of function, while entangled amyloid pla-ques exert minimal biological activity.
Smith, R. A. S., Nabok, A., Blakeman, B. J. F., Xue, W. F., Abell, B., & Smith, D. P. (2015). Analysis of toxic amyloid fibril interactions at natively derived membranes by ellipsometry. PLoS ONE, 10(7). https://doi.org/10.1371/journal.pone.0132309