Membrane-Modulating Drugs can Affect the Size of Amyloid-β25–35 Aggregates in Anionic Membranes Journal Articles uri icon

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abstract

  • AbstractThe formation of amyloid-βplaques is one of the hallmarks of Alzheimer’s disease. The presence of an amphiphatic cell membrane can accelerate the formation of amyloid-βaggregates, making it a potential druggable target to delay the progression of Alzheimer’s disease. We have prepared unsaturated anionic membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) and added the trans-membrane segment Aβ25–35. Peptide plaques spontaneously form in these membranes at high peptide concentrations of 20 mol%, which show the characteristic cross-βmotif (concentrations are relative to the number of membrane lipids and indicate the peptide-to-lipid ratio). We used atomic force microscopy, fluorescence microscopy, x-ray microscopy, x-ray diffraction, UV-vis spectroscopy and Molecular Dynamics (MD) simulations to study three membrane-active molecules which have been speculated to have an effect in Alzheimer’s disease: melatonin, acetylsalicyclic acid (ASA) and curcumin at concentrations of 5 mol% (drug-to-peptide ratio). Melatonin did not change the structural parameters of the membranes and did not impact the size or extent of peptide clusters. While ASA led to a membrane thickening and stiffening, curcumin made membranes softer and thinner. As a result, ASA was found to lead to the formation of larger peptide aggregates, whereas curcumin reduced the volume fraction of cross-βsheets by ~70%. We speculate that the interface between membrane and peptide cluster becomes less favorable in thick and stiff membranes, which favors the formation of larger aggregates, while the corresponding energy mismatch is reduced in soft and thin membranes. Our results present evidence that cross-βsheets of Aβ25–35in anionic unsaturated lipid membranes can be re-dissolved by changing membrane properties to reduce domain mismatch.

publication date

  • August 17, 2018