Abstract
The formation of amyloid-β plaques is one of the hallmarks of Alzheimer’s disease. The presence of an amphiphatic cell membrane can accelerate the formation of amyloid-β aggregates, 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-β motif (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-β sheets 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-β sheets of Aβ25–35 in anionic unsaturated lipid membranes can be re-dissolved by changing membrane properties to reduce domain mismatch.
Highlights
A primary feature in the pathogenesis of Alzheimer’s disease is the deposition of insoluble fibrillar plaques in the extracellular space of brain tissue[1]
As the membrane may play an integral role in plaque formation, we studied three membrane-active molecules: curcumin, acetylsalicyclic acid (ASA), and melatonin, with Aβ25–35
As all drugs investigated in this study do not directly interact with the amyloid peptides but instead impact on membrane properties, it is likely that membrane-mediated interactions between the inserted proteins play a major role in the aggregation behaviour of Aβ25–35
Summary
A primary feature in the pathogenesis of Alzheimer’s disease is the deposition of insoluble fibrillar plaques in the extracellular space of brain tissue[1]. Amyloid-β is a polypeptide consisting of 42 amino acids, which has a 10 amino acid long transmembrane segment, Aβ25–35, that is common to both the amyloid precursor protein (APP) and the full length Aβ peptide While this short transmembrane segment is commonly used in the study of peptide interactions and partitioning in membranes, see for example[4,5,6], it has been reported to have neurotoxic properties[7,8,9,10,11,12] and high tendency for aggregation and fibrillation[13,14,15]. In Alzheimer’s disease, the monomeric Aβ peptides transition into long, peptide structures that form amyloid fibres These fibres consists of arrays of β sheets running parallel to the long axis of the fibrils, the cross-β motif[17], which are connected through steric zippers[1]. Many of these molecules have known membrane interactions leading to changes in fluidity, thickness, and bending stiffness which could, in turn, influence peptide aggregation[31]
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