Neuroprotective Effect of Alpha-Linolenic Acid against Aβ-Mediated Inflammatory Responses in C6 Glial Cell

Therapeutic approaches for neurodegeneration, such as Alzheimer's disease (AD), have been widely studied. One of the critical hallmarks of AD is accumulation of amyloid beta (A beta). A beta induces neurotoxicity and releases inflammatory mediators or cytokines through activation of glial cell, and these pathological features are observed in AD patient's brain. The purpose of this study is to investigate the protective effect of alpha-linolenic acid (ALA) on A beta(23-35)-induced neurotoxicity in C6 glial cells. Exposure of C6 glial cells to 50 mu M A beta(25-35) caused cell death, overproduction of nitric oxide (NO), and proinflammatory cytokines release [interleukin (IL)-6 and tumor necrosis factor-alpha], while treatment of ALA increased cell viability and markedly attenuated A beta(25-35)-induced excessive production of NO and those inflammatory cytokines. Inhibitory effect of ALA on generation of NO and cytokines was mediated by down-regulation of inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expressions. In addition, ALA treatment inhibited reactive oxygen species generation induced by A beta(25-35) through the enhancement of the nuclear factor-erythroid 2-related factor-2 (Nrf-2) protein levels and subsequent induction of heme-oxygenase-1 (HO-1) expression in C6 glial cells dose- and time-dependently. Furthermore, the levels of neprilysin and insulin-degrading enzyme protein expressions, which contribute to degradation of A beta, were also increased by treatment of ALA compared to A beta(23-35)-treated control group. In conclusion, effects of ALA on A beta degradation were shown to be mediated through inhibition of inflammatory responses and activation of antioxidative system, Nrf-2/HO-1 signaling pathway, in C6 glial cells. Our findings suggest that ALA might have the potential for therapeutics of AD.