The Curcumin Derivative GT863 Protects Cell Membranes in Cytotoxicity by A beta Oligomers

In Alzheimer's disease (AD), accumulation of amyloid beta-protein (A beta) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by A beta has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce A beta-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic A beta oligomers (A beta o), which include high-molecular-weight (HMW) A beta o, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 mu M) on A beta o-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca2+ ([Ca2+]i). GT863 inhibited the A beta o-induced increase in plasma-membrane phospholipid peroxidation, decreased membrane fluidity and resistance, and decreased excessive [Ca2+]i influx, showing cytoprotective effects. The effects of GT863 on cell membranes may contribute in part to its neuroprotective effects against A beta o-induced toxicity. GT863 may be developed as a prophylactic agent for AD by targeting inhibition of membrane disruption caused by A beta o exposure.