Effects Of Acetaldehyde On Tau Phosphorylation In SH-SY5Y Cells And The Underlying Mechanisms

Excessive alcohol intake or metabolic disorders can lead to the accumulation of acetaldehyde that damages digestive system,immune system,and nervous system.Studies have shown that alcoholics are more likely to suffer from various neurodegenerative diseases than nondrinkers.Tau is a microtubule-associated protein important for regulating microtubule assembly and stability.Abnormal hyperphosphorylation of tau decreases its microtubule-binding capacity and disrupts microtubule stability.The disintegration of the microtubules system causes the decline of the axonal transport,resulting in the loss of the axon function and even neuronal death.The hyperphosphorylated tau aggregated into straight filaments and paired helical filaments,which form NFTs in the neurons of patients with neurodegenerative diseases including Alzheimer’s disease（AD）.However,the effect of acetaldehyde accumulation in vivo on tau phosphorylation has yet to be studied.In this study,Western Blot and ROS detection methods were used to study the effect of acetaldehyde on tau phosphorylation and the underlying mechanisms in human neuroblastoma SH-SY5Y cells.The results showed that acetaldehyde increased tau phosphorylation at Ser202/Tyr205 in a concentration（20-50μM）and time dependent（4-8 h）manner.The phosphorylation of p38 mitogen-activated protein kinase（MAPK）and c-Jun amino terminal kinase（JNK）were increased in cells treated with acetaldehyde（by 90.7%and 33.9%respectively）.At the same time,inhibitors of p38 MAPK and JNK reduced the phosphorylation of tau（decreased by 46.6.7%and 59.96%respectively）.The data also showed that acetaldehyde incubation could induce the production of reactive oxygen species（ROS）.Moreover,the phosphorylation of tau and the activation of p38 MAPK and JNK were decreased when ROS production was inhibited by N-acetyl-L-cysteine（NAC）.Acetaldehyde incubation also increased the phosphorylation of tau protein at another important site,serine 396（51.25%）.At the same time,glycogen synthase kinase 3 beta（GSK3β）was activated and the intracelluar level of Ca²⁺was increased significantly.Above results indicated that acetaldehyde might induce the activation of p38 MAPK and JNK by increasing the production of ROS,which further induces the phosphorylation of tau.Acetaldehyde also increased the phosphorylation of tau at serine 396,which might be associated with the activation of GSK3βinduced by the imbalance of intracellular calcium homeostasis.