Nrf2 Regulates Tau Clearance: An Alzheimer’s Disease Treatment Strategy
Our study will look at on how normal brain cells get rid of excess tau protein, and how we might be able to “restart” that vital function during Alzheimer’s disease. This is important because in Alzheimer disease, the buildup of tau protein contributes to the poor functioning and eventual death of the nerve cell. Cells normally identify proteins that are no longer needed, and then engulf and digest them, through a system called “autophagy.” However, as the brain struggles with Alzheimer’s disease, that system of autophagy does not work as efficiently as it once did. Finding ways to selectively target tau protein for clearance by autophagy could be beneficial. One approach is to upregulate proteins that make the process work better and directly deliver tau to the autophagy machinery. We have found that chemicals contained in certain foods, such as broccoli and green tea, can increase autophagy and decrease tau levels. In this project, we will determine how these types of chemicals improve the ability of nerve cells to get rid of excess or damaged tau protein, studying the process both in vitro (ie, in nerve cells grown in dishes) and in vivo (ie, in living organisms, in this case in mice). These studies will help us understand how a nerve cell normally gets rid of unwanted tau protein, what might be going wrong with this “disposal system” in Alzheimer disease, and what we can do to make it work better.
This project focuses on how to more effectively reduce the levels of the tau protein in brain cells, with the long-term goal of developing a possible treatment for Alzheimer disease. The first aim of this project is to determine how activation of the regulatory protein Nrf2 may be important in tagging tau for destruction by a specific degradation pathway called autophagy. Nrf2 is activated by “good” chemicals in our diet that are found in cruciferous vegetables, including broccoli, Brussels sprouts and kale, as well as in green tea. When Nrf2 is activated by these chemicals, it tells the cell to make more of certain proteins that help the cell handle stress. We have previously found that one protein that is increased by Nrf2 is NDP52, and this protein plays a role in delivering tau to autophagy for destruction. Thus, we will be trying to find the best chemicals for increasing Nrf2 activity and NDP52 expression, determining how NDP52 delivers tau to autophagy, and also looking for ways to make this process more efficient. For the first objective, we will be carrying out experiments in brain cells grown in special cultures in petri dishes in the laboratory.
Next, in order fully understand how Nrf2 affects tau removal and then investigate that as a treatment strategy, we need to carry out studies in living brains. Therefore as the second aim of this proposal, we will determine how Nrf2 functions in the mouse brain. For these experiments, we will use regular mice and mice that have been genetically engineered not to express Nrf2. Studying these mice, we will determine if the lack of Nrf2 results in increased accumulation of tau in brain cells and also if the lack of Nrf2 affects the autophagy protein destruction system. We are very excited about these studies, as we believe we are exploring a novel mechanism that may provide the basis for effective treatment strategy in the fight against Alzheimer disease. Once we understand the role of these naturally-derived chemicals in facilitating the reduction of tau protein, future investigations could involve experimental use of pharmaceuticals to do the same thing, but more efficiently, in the brain.