Biophysical Society Thematic Meeting - October 13-15, 2015

Biophysics of Proteins at Surfaces: Assembly, Activation, Signaling

Thursday Speaker Abstracts

GM 1 Nanodomains Inhibit the Oligomerization of Membrane Bound ß-amyloid Monomers Mariana Amaro 1 , Radek Sachl 1 , Gokcan Aydogan 1 , Ilya I. Mikhalyov 2 , Martin Hof 1 . 1 J. Heyrovský Institute of Physical Chemistry of the C.A.S. v.v.i., Prague, Prague 8, Czech Republic, 2 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the R.A.S., Moscow, Russian Federation. Oligomers of ß-amyloid (Aß) are thought to spark neuronal dysfunction, cell death and Alzheimer disease onset. 1 The monosialoganglioside GM 1 has been suggested to seed aggregation of Aßand thus enhance the formation of Aß's cytotoxic oligomers. 2 However, such studies are commonly performed in system with high concentrations of GM 1 , sphingomyelin, cholesterol, and amyloid peptides, thus their pertinence to the physiological oligomerization of Aß on cellular membranes might be low. In this work, we strive to emulate more physiological conditions. The oligomerization of Aß on lipid bilayers containing essential components of the neuronal plasma membrane is addressed using the single molecule sensitivity of fluorescence. The oligomerization of Aß is characterized by changes of its lateral diffusion coefficient and by Cross-Correlation Fluorescence Correlation Spectroscopy. 3 A novel Fluorescence Lifetime Förster Resonance Energy Transfer approach 4 is used to characterize heterogeneities on the nanometer scale in lipid bilayers. We find that sphingomyelin is a key trigger for the in-membrane oligomerization of Aß monomers. Physiological levels of GM 1 , organized in nanodomains, do not seed Aß's oligomerization. Moreover, GM 1 counteracts the effect of sphingomyelin and prevents the oligomerization of Aß. This molecular evidence for GM 1 as an inhibitor of the oligomerization of Aß supports the idea of GM 1 as a protective factor 5 , rather than GM 1 as an enhancer of the toxic oligomerization of Aß. 1 K. A. Conway, et al. PNAS 97 (2000); M. Bucciantini, et al. Nature 416 (2002); G. M. Shankar, et al. Nat. Med. 14 (2008) 2 K. Yanagisawa, J. Neurochem. 116 (2011) 3 A. Benda, et al. Langmuir 19 (2003); F. Heinemann, et al. Langmuir 28 (2012); R. Machan, M. Hof, Biochim. Biophys. Acta 1798 (2010). 4 R. Sachl, et al. BBA-Mol. Cell Res. 1853 (2015) 5 F. Kreutz, et al. Neurochem Res. 38 (2013)

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