Acetaldehyde induces tau phosphorylation via activation of p38 MAPK/JNK and ROS production

Heavy drinking has been associated with increased risk of dementia such as Alzheimer’s disease, but the mechanisms are not fully understood. Evidence suggests that acetaldehyde, the most toxic metabolite of ethanol, mediates the brain tissue damages and cognitive dysfunction induced by the overconsumption of alcohol. Abnormal hyperphosphorylated tau protein is the major component of neurofibrillary tangle that correlates with neurodegeneration. However, there are few reports regarding whether acetaldehyde affects the phosphorylation of tau protein in neuronal cells. The aim of this study is to explore the effect of acetaldehyde on the phosphorylation of tau protein. It was found that acetaldehyde treatment increased the amount of phosphorylated tau in human neuroblastoma SH-SY5Y cells. Further studies revealed that acetaldehyde increased the production of reactive oxygen species (ROS) and induced the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Pretreatment with antioxidant N-acetylcysteine (NAC) or inhibitors of p38 MAPK and JNK ameliorated the phosphorylation of tau in acetaldehyde treated cells, suggesting that acetaldehyde might increase the phosphorylation of tau via inducing the production of ROS and activating p38 MAPK and JNK pathways. The result indicated that acetaldehyde treatment increased tau phosphorylation in neuronal cells. Therefore, the accumulation of acetaldehyde resulted from alcohol abuse or defect of acetaldehyde detoxification may promote tau pathology in neurodegenerative diseases such as AD.