The Curcumin Derivative GT863 Protects Cell Membranes in Cytotoxicity by Aβ 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.

Automated summary

The protective mechanism of GT863 against the neurotoxicity of A beta oligomers (A beta o) was investigated in this study. GT863 inhibited A beta o-induced membrane damage by reducing phospholipid peroxidation, decreasing membrane fluidity and resistance, and reducing excessive intracellular calcium influx. These findings suggest that GT863 exerts cytoprotective effects by targeting membrane disruption caused by A beta o exposure and could be developed as a prophylactic agent for Alzheimer's disease (AD).