Curcumin Reduces Amyloid Beta Oligomer Interactions with Anionic Membranes

Many neurodegenerative diseases involve amyloidogenic proteins forming surface-bound aggregates on anionic membranes, and the peptide amyloid β (Aβ) in Alzheimer's disease is one prominent example of this. Curcumin is a small polyphenolic molecule that provides an interesting opportunity to understand the fundamental mechanisms of membrane-mediated aggregation because it embeds into membranes to alter their structure while also altering Aβ aggregation in an aqueous environment. The purpose of this work was to understand interactions among curcumin, β-sheet-rich Aβ fibrillar oligomers (FO), and a model anionic membrane. From a combination of liquid surface X-ray scattering experiments and molecular dynamics simulations, we found that curcumin embedded into an anionic 1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG) membrane to rest between the lipid headgroups and the tails, causing disorder and membrane thinning. FO accumulation on the membrane was reduced by ∼66% in the presence of curcumin, likely influenced by membrane thinning. Simulation results suggested curcumin clusters near exposed phenylalanine residues on a membrane-embedded FO structure. Altogether, curcumin inhibited FO interactions with a DMPG membrane, likely through a combination of altered membrane structure and interactions with the FO surface. This work elucidates the mechanism of curcumin as a small molecule that inhibits amyloidogenesis through a combination of both membrane and protein interactions.