Curcumin tautomerization in the mechanism of pentameric amyloid- ß42 oligomers disassembly.

ABSTRACT

Alzheimer's disease is a neurologic disorder characterized by the accumulation of extracellular deposits of amyloid-ß (Aß) fibrils in the brain of patients. The key etiologic agent in Alzheimer's disease is not known; however oligomeric Aß appears detrimental to neuronal functions and increases Aß fibrils deposition. Previous research has shown that curcumin, a phenolic pigment of turmeric, has an effect on Aß assemblies, although the mechanism remains unclear. In this study, we demonstrate that curcumin disassembles pentameric oligomers made from synthetic Aß42 peptides (pentameric oAß42), using atomic force microscopy imaging followed by Gaussian analysis. Since curcumin shows keto-enol structural isomerism (tautomerism), the effect of keto-enol tautomerism on its disassembly was investigated. We have found that curcumin derivatives capable of keto-enol tautomerization also disassemble pentameric oAß42, while, a curcumin derivative incapable of tautomerization did not affect the integrity of pentameric oAß42. These experimental findings indicate that keto-enol tautomerism plays an essential role in the disassembly. We propose a mechanism for oAß42 disassembly by curcumin based on molecular dynamics calculations of the tautomerism. When curcumin and its derivatives bind to the hydrophobic regions of oAß42, the keto-form changes predominantly to the enol-form; this transition is associated with structural (twisting, planarization and rigidification) and potential energy changes that give curcumin enough force to act as a torsion molecular-spring that eventually disassembles pentameric oAß42. This proposed mechanism sheds new light on keto-enol tautomerism as a relevant chemical feature for designing such novel therapeutic drugs that target protein aggregation.