Traumatic brain injury disrupts brain drainage and accelerates Alzheimer’s risk

University of Virginia School of Medicine researchers have uncovered how and why traumatic brain injury (TBI) increases the risk for Alzheimer's disease, and their work suggests a potential way to prevent that increased risk.

John Lukens, PhD, director of UVA's Harrison Family Translational Research Center in Alzheimer's and Neurodegenerative Diseases, and his collaborators found that a single mild TBI brings about harmful changes in the brain that facilitate the onset of Alzheimer's. But they also were able to prevent those changes in lab mice by using a hollowed-out virus to deliver repair supplies into the brain's protective membranes.

"Our findings indicate that fixing brain drainage following head trauma can provide a much-needed strategy to limit the development of Alzheimer's disease later in life," said Lukens, part of UVA's Department of Neuroscience and its Center for Brain Immunology and Glia (BIG Center). "Our hope is that these discoveries will inspire the design of novel brain drainage-boosting therapeutics that can be deployed to accelerate recovery of the injured brain and limit the risk of developing Alzheimer's disease."

TBI and Alzheimer's disease

Traumatic brain injuries are known to increase the risk for Alzheimer's and other neurodegenerative diseases significantly, but scientists have had little understanding of why. Lukens' new research suggests that such injuries impair the function of lymphatic vessels that connect the brain and the immune system. These vessels, located in the brain's protective membranes (or "meninges"), were thought not to exist until they were discovered by UVA neuroscience researchers in 2015. Now the vessels are known to play a vital role in cleaning and protecting the brain.

Lukens' work suggests TBI accelerates the accumulation of harmful tau protein associated with Alzheimer's disease, and that these tau tangles are not necessarily confined to the site of the injury. In lab mice, a single mild TBI worsened overall brain health and spurred neurodegeneration. 

The scientists were able to identify specific effects caused by mild TBI, including harmful changes to the activity of immune cells called macrophages that act as brain defenders and debris removers.

This research builds on our understanding of some of the devastating long-term outcomes after brain injury and how they pertain to neurodegenerative disease. Traumatic brain injury is a condition where we have very few medical interventions currently, so a prospective therapeutic target is very exciting."

Ashley Bolte, MD, PhD, medical doctor at UVA and member of the research team

Promisingly, the scientists found they could act within 24 hours of an injury to protect the brain and restore the function of the vital lymphatic vessels. They used a hollowed-out virus shell to deliver a substance called VEGFC directly into the meninges. This "lymphatic growth factor" is naturally produced in the body to promote vessel growth and repair, and administering it to the meninges prevented harmful tau production.

Much more research will be needed before the approach could be used as a treatment in people, but the scientists say it holds exciting promise for preventing TBI-related neurodegeneration. This could help stave off not just Alzheimer's but other neurological diseases, the researchers say.

"Traumatic brain injury has also been linked to multiple other neurodegenerative disorders, including ALS, Parkinson's disease and chronic traumatic encephalopathy [CTE]," Lukens said. "Exploring whether recuperating brain drainage following head trauma is also effective in protecting against these other devastating neurodegenerative diseases will be an important future area of investigation for our lab and others."

Finding new ways to prevent and treat Alzheimer's and other neurodegenerative diseases is a top priority for UVA's Paul and Diane Manning Institute of Biotechnology, the home to Lukens' Alzheimer's research center. The institute aims to accelerate the development of new treatments and cures for some of the most complex and devastating diseases, with the goal of providing hope and longer, healthier lives for patients across Virginia and beyond.

Findings published

The researchers have published their findings in the scientific journal Cell Reports. The research team consisted of Marco, Katherine R. Bruch, Maureen N. Cowan, Julia G. Dill, Katelyn A. Moore, Ashley C. Bolte and Lukens. The scientists have no financial interest in the work.

The research was supported by the U.S. Department of Defense, grant W81XWH2110788; the Alzheimer's Association, grant ADSF-21-816651; the National Institutes of Health's National Institute of Neurological Disorders and Stroke, grant R01NS106383; the Owens Family Foundation; a Steven A. Newman AD Award; the Rick Sharp Foundation; and the Harrison Family Foundation.