Alzheimer’s disease (AD) is a devastating and progressive neurodegenerative disease and is attributed to a number of factors such as the cholinergic dysfunction, oxidative stress/mitochondrial dysfunction and accumulation of amyloid beta (Aβ) and the hyperphosphorylation of tau proteins in the brain. Formation of amyloid-beta species is associated with the gradual decline in cognition leading to dementia.
There is compelling evidence that phosphorylated tau play a crucial role as a mediator of Aβ toxicity generating a growing interest in finding molecules which are able to increase the clearance of tau in neurons as a therapeutic strategy for treating AD.
Tau appears to be mainly cleared by autophagy. Nrf2 is believed to be essential in this. Interestingly, fisetin not only activates Nrf2, but also inhibits the activity of mTOR kinase. Normally when a cell is stressed or starved mTORC1 is inactivated enabling TFEB, which is considered a master regulator of autophagy, to move into the nucleus, where it coordinates the expression of autophagy and lysosomal genes, and stimulating lysosomal biogenesis. A recent study also showed that TFEB promotes the clearance of aberrant tau species and rescues behavioral and synaptic deficits in a mouse model.
In this study the researchers therefore hypothesized that fisetin could promote the degradation of phosphorylated tau by enhancing autophagy through increasing the transcriptional activity of TFEB and Nrf2. To verify this theory they setup up an in-vitro experiment. Primary cortical neuronal cultures from rat embryonic forebrain were prepared and exposed to fisetin in various conditions.
It was found that treatment of cortical cells or primary neurons with fisetin resulted in significant decreases in the levels of phosphorylated tau. In addition, fisetin decreased the levels of sarkosyl-insoluble tau. However, there was no difference in activities of tau kinases and phosphatases, irrespective of fisetin treatment indicating that tau decrease likely needs to occur via increased autophagy. The test data showed Fisetin activated autophagy together with the activation of transcription factor EB (TFEB) and Nrf2 transcriptional factors. The mechanism of autophagy activation is likely due to rapamycin complex 1 (mTORC1) inhibition, since the phosphorylation levels of relevant enzymes were decreased in the presence of fisetin.
Together the results indicate that fisetin reduces levels of phosphorylated tau and suggest that fisetin is a potential preventive and therapeutic drug candidate for Alzheimer’s disease.