Melatonin reduces GSK3β expression and tau phosphorylation via Nrf2 nuclear translocation

Abstract

Alzheimers disease is a neuropathological condition with abnormal formation of extracellular Amyloid-{beta} plaques and intracellular neurofibrillary tangles (NFTs) of Microtubule-associated protein Tau (Tau) in brain. In pathological condition, MAP-Tau can undergo various post-translational modifications such as hyperphosphorylation by the activity of cellular kinases which eventually leads to protein aggregation in neurons. Melatonin is a hormone which mainly secreted from pineal gland, functions to modulate cellular kinases. In our study, we elucidated that Melatonin has inhibited the Tau aggregates mediated cytotoxicity and membrane leakage by MTT and LDH assay respectively in neuro2A cells. Melatonin has found to reduce the GSK3{beta} mRNA expression and protein level by western blot and immunofluorescence assay. Melatonin has also decreased phospho-Tau level (pThr181 and pThr212-pSer214) in neuron cell line upon OA induction as seen by microscopic analysis.. Melatonin treatment has associated with ROS quenching by DCFDA assay, reduced caspase 3 activity in neuronal cells. Further, Melatonin has increased Nrf2 level and nuclear translocation as oxidative stress response in Tauopathy. Together, these findings clearly signifies that Melatonin remediate the Tau-induced neuronal cytotoxicity and reduce Tau hyperphosphorylation via downregulating GSK3{beta} expression. Melatonin can combat oxidative damage by Nrf2 activation and nuclear translocation in AD condition.