Is Failure of Glymphatic Tau Clearance a Critical Pathophysiological Event in CTE?
Abstract
The lymphatic system is a network of vessels that collect fluid from tissue. The lymphatic system is mostly known for its role in the immune system, but it also plays a key role in removal of waste products, which it clears to the general blood circulation. The brain and spinal cord lack a lymphatic system, despite being the most active tissue in our body and being very sensitive to changes in its internal environment. Remarkably, this paradox has never prompted a systematic analysis of how the brain removes potentially toxic byproducts of activity on an organ level -- there is no known "lymphatic system of the brain." This is surprising because many neurological diseases like traumatic brain injury and Alzheimer s disease are thought to involve the failure of protein (including the protein called "tau") clearance from the brain. We have identified a fundamentally novel anatomical pathway for the clearance of fluid and protein, including tau, from the brain. Our studies show that waste products such as tau are flushed out of the brain by a stream of fluid flow that moves through the brain tissue, particularly along blood vessels. This fluid movement is supported by brain water channels (AQP4 channels) that are present in the supportive cell of the brain, astroglial cells. Because this pathway functions like the lymphatic system and depends on these glial cells, we have termed this novel clearance pathway the "glymphatic" system. Our preliminary studies indicate that traumatic brain injury in mice triggers a sustained decrease in protein clearance along this pathway, including reducing tau clearance. The proposed studies will, by using several alternative approaches, define the importance of this glymphatic pathway in the removal of tau. We will also develop a diagnostic test that can provide valuable information on how suppression in glymphatic function after TBI may lead to Alzheimer s disease. The proposed studies may provide entirely new targets for the treatment or even cure of cognitive impairments in Service men or women after traumatic brain injury. Increasing the ability of the glymphatic pathway to clear waste products, including tau, after traumatic brain injury may prevent the damaging accumulation of these proteins that lead to these cognitive problems and Alzheimer s disease. Even more important, increasing the efficiency of these clearance pathways may enable established "clumps" of protein within the brain to be reduced or even eliminated, thus enabling the treatment of the large number of military personnel and others who are already suffering from cognitive and psychological decline after traumatic brain injury. We hope to have defined the diagnostic platform within the next 3-4 years. We plan to submit an initial application for a safety trial at that time and at 5-6 years a full application. University of Rochester has the infrastructure and the expertise to quickly translate these exciting preclinical observations so that they can be used in the clinic. Karl Kieburtz, MD, MPH, is the Director of the Center for Human Experimental Therapeutics (CHET) at the University of Rochester Medical Center (URMC). CHET conducts learning phase clinical trials in a wide spectrum of disorders in collaboration with investigators within the URMC as well as with centers throughout North America, Europe, Asia, and Oceania. Dr. Kieburtz is a nationally recognized clinical trial investigator. He plans to initiate a multi-center, collapsed, clinical trial if our preclinical studies bear out. Thus, the University of Rochester is well-positioned to coordinate a multicenter academic trial of agents that can promote tau clearance after traumatic brain injury, and it can do so quite economically at cost, leveraging its existent administrative infrastructure. To our knowledge, these studies represent the first analysis of how tau is cleared from the brain on an organ level and the investigation of how tra
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610555
Entities
People
- Maiken Nedergaard
Organizations
- United States Army
- University of Rochester