Protein misfolding and aggregation is associated with many neuropathic and non-neuropathic diseases, including Alzheimer’s disease (AD) and type-2 diabetes (T2D). Aggregation and amyloid formation of β-amyloid and amylin (or IAPP) are implicated in AD and T2D, respectively. While, the underlying mechanisms are unclear, increasing evidence suggests that (i) the biological membrane plays a central role in catalyzing amyloid aggregation and severity of pathological conditions, (ii) the amyloid intermediates are toxic and are potential therapeutic targets. Nanodiscs comprising of a lipid bilayer surrounded by a belt made up of amphipathic polymers or peptides is valuable to investigate and to control amyloid aggregation in a membrane environment. Here, we show the designing and optimization of lipid-nanodiscs and their use to better understand amyloid aggregation at the membrane interface. Our results show a varying lipid composition combined with the physical and chemical properties of the nanodiscs belt is essential to trap and stabilize amyloid oligomers. Through utilizing NMR spectroscopy and other biophysical techniques, we are able to examine the structural details of β-amyloid intermediates trapped by the nanodiscs. Nevertheless, through fine-tuning the chemical and physical properties of the lipids and the belt in nanodiscs, we have succeeded in controlling the pathological phenotypes of amyloid intermediates. We also compared the binding of amylin to a polymer (PMAQA) and ApoA-I fragment (4F peptide) encased nanodiscs (≈10 nm) composed of identical lipids (DMPC:DMPG=4:1). Heteronuclear NMR experiments reveal a slow and fast dynamics in amylin interacting with 4F- and PMAQA-nanodiscs, respectively, indicating its selective lipid (in 4F-nanodiscs) and belt (in PMAQA-nanodiscs) interactions. Further testing confirmed the selective binding activity of the nanodiscs belt in lipid-dissociated state against β-amyloid and amylin aggregation. These findings can be used in the design of new multifunctional materials for future studies of amyloid-related diseases. 

Nanodiscs: Useful tool to probe protein misfolding and amyloid aggregation

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.