Researchers at The Ohio State University Wexner Medical Center and College of Medicine have investigated the molecular factors that might elevate the risk of developing Alzheimer’s disease after experiencing a traumatic brain injury (TBI), utilizing both mouse models and human brain tissue obtained after death.
Every year, approximately 2.5 million individuals experience traumatic brain injuries (TBI), which often leads to a heightened likelihood of developing Alzheimer’s disease as they age.
The research team focused on understanding the mechanisms that connect TBI with the onset of Alzheimer’s disease. “Given the high rates of TBI and Alzheimer’s in the population, it is crucial to learn about the molecular mechanisms linking them to create effective treatments to mitigate this risk,” explained Hongjun “Harry” Fu, PhD, the senior author of the study and assistant professor of neuroscience at Ohio State.
The findings of this study are available in the journal Acta Neuropathologica.
The researchers discovered that TBI leads to an increase in hyperphosphorylated tau, as well as astro- and microgliosis, which are linked to synaptic dysfunction and cognitive decline associated with Alzheimer’s. They also identified that decreased levels of BAG3, a protein important for clearing proteins through the autophagy-lysosome pathway, play a role in the buildup of hyperphosphorylated tau in neurons and oligodendrocytes following TBI in both mouse models and human tissue from individuals with a history of TBI.
By using a method to overexpress BAG3 in neurons, the researchers found that this overexpression improves tau hyperphosphorylation, synaptic issues, and cognitive deficits, likely by enhancing the autophagy-lysosome pathway.
“Our findings suggest that targeting neuronal BAG3 may be a promising treatment approach to prevent or lessen the Alzheimer’s-like pathology,” said Nicholas Sweeney, the study’s first author and a neuroscience research assistant at Ohio State.
This study builds on previous work that identified BAG3 as a key gene regulating tau levels from healthy human brain tissue. According to Tae Yeon Kim, a PhD student in Ohio State’s Biomedical Sciences Graduate Program and co-first author of the study, BAG3 could be an important factor in the brain’s susceptibility to tau-related pathology in Alzheimer’s.
“Given that past research indicates an increase in tau pathology following TBI, we suspected that BAG3 might contribute to this accumulation,” said Fu. “Our results confirmed that dysfunction of BAG3 disrupts protein clearance processes, leading to tau buildup in both mouse models and human brain tissue that have experienced TBI and Alzheimer’s.”
Future studies will seek to confirm the connection between TBI, BAG3, tau pathology, gliosis, and neurodegeneration, utilizing a novel TBI model called the Closed Head Induced Model of Engineered Rotational Acceleration (CHIMERA), which simulates common mild TBI scenarios found in humans, according to Fu.
“Completing these future studies will provide deeper insights into how TBI and Alzheimer’s are biologically related and could help in creating innovative therapies to lower the risk of Alzheimer’s following a TBI,” he stated.
The research team included experts from Ohio State, Arizona, New York, West Virginia, and Japan.
This study was funded by the Department of Defense, the National Institute on Aging at the National Institutes of Health, a seed grant from the Neurological Research Institute at The Ohio State University, and the Summer Undergraduate Research Fellowship from The Ohio State University’s Chronic Brain Injury Discovery Theme.
The authors report no conflicts of interest.
