How Does Nanodiscs Modulate A1-40 Fibrillation

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Nanodiscs modulates A1-40 fibrillation Biological membranes were shown to modulate the A1-40 aggregation and pathways depending on their physical and chemical properties. Here, we observed the effect of membrane variable nanodiscs in modulating the kinetics of A1-40 using ThT fluorescence dye. The formation of nanodiscs with different lipid compositions were achieved by varying the lipid to PMA concentration (see methods). The DLS measurements ensures a hydrodynamic diameter ranging from ~ 7 to 12 nm for the targeted nanodisc systems (Fig 1a). For a comparative analysis and as per the suitability of PMA for nanodisc formation, we used the 1,2-dimyristoyl-sn-glycero-3 lipids for our analysis. To formation of nanodiscs by PMA is further …show more content…

We observed some atypical ThT fluorescence curves with multiple peaks for few nanodisc systems as shown in Fig 1c at low lipid concentration. We speculated a possible structural rearrangement of A fibers (disintegration) occur after binding to nanodiscs resulting in the ThT quenching during the reaction due to an inherent nature of off pathway unstable protofibers and/or oligomers. Rapid sheet induction in A1-40 by Nanodiscs The secondary structural transition of A1-40 form a random coil conformation to a metastable sheet structure during self-seeding reaction is a ubiquitous phenomenon. Here, we investigated the effect of nanodiscs on the conformational change of A1-40 at variable lipid composition and concentration. The CD spectra of A1-40 showed its rapid transition from a random coil to sheet conformation irrespective of the membrane composition in the nanodisc system (Fig 2a). Current therapeutic strategies in AD focus on the inhibition of toxic oligomer intermediates of A1-40 which typically shows a mixed  conformation (ref). Our CD results showed a typical sheet conformation for A1-40 that corresponds to a matured fiber structure (Fig 2a). However, the ThT results of the corresponding titration (Fig 1c) showed inhibition of A1-40 aggregation and amyloid fiber

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