The Interaction between Amyloid-β Peptides and Anionic Lipid Membranes Containing Cholesterol and Melatonin

One of the hallmarks of Alzheimer's disease is the formation of senile plaques, primarily consisting of amyloid-[Image: see text] (A[Image: see text]) peptides. Peptide-membrane and peptide-lipid interactions are thought to be crucial in this process. We studied the interaction of A[Image: see text] and A[Image: see text] peptides with anionic lipid membranes made of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphoserine (DMPS) using X-ray diffraction. We compare the experimentally determined electron densities in the gel state of the membranes with density calculations from peptide structures reported in the Protein Data Bank in order to determine the position of the peptide in the bilayers. The full length peptide A[Image: see text] was found to embed in the hydrocarbon core of the anionic lipid bilayers. Two populations were found for the A[Image: see text] peptide: (1) membrane-bound states in the hydrophilic head group region of the bilayers, where the peptides align parallel to the membranes, and (2) an embedded state in the bilayer center. Aging plays an important role in the development of Alzheimer's, in particular with respect to changes in cholesterol and melatonin levels in the brain tissue. Immiscible cholesterol plaques were created by addition of 30 mol% cholesterol to the anionic membranes. The A[Image: see text] peptides were found to strongly interact with the lipid bilayers, displacing further cholesterol molecules into the plaques, effectively lowering the cholesterol concentration in the membranes and increasing the total fraction of cholesterol plaques. Addition of 30 mol% melatonin molecules to the anionic membranes drastically reduced the population of the membrane-embedded A[Image: see text] state. These results present experimental evidence for an interaction between A[Image: see text] peptides, melatonin and cholesterol in lipid membranes.