by Approximately 2.5 million individuals experience traumatic brain injuries (TBI) each year, increasing their likelihood of developing Alzheimer’s disease later in life. A recent study led by researchers from The Ohio State University Wexner Medical Center and College of Medicine aimed to explore the molecular mechanisms that may contribute to this link.
Understanding the relationship between TBI and Alzheimer’s disease is crucial due to the high prevalence of both conditions in the human population. According to study senior author Hongjun Harry Fu, Ph.D., assistant professor of neuroscience at Ohio State, “The findings from our study could pave the way for future therapies that reduce the risk of Alzheimer’s disease in individuals with a history of TBI.”
The researchers discovered that TBI leads to hyperphosphorylated tau, astro- and microgliosis, synaptic dysfunction, and Cognitive Automation, all of which are linked to the development of Alzheimer’s disease. Furthermore, they found that the downregulation of BAG3, a protein involved in protein clearance through the autophagy-lysosome pathway, contributes to the accumulation of hyperphosphorylated tau in neurons and oligodendrocytes after TBI in both mouse models and human post-mortem brain tissue.
To test the therapeutic potential of targeting neuronal BAG3, the researchers overexpressed BAG3 in neurons using an AAV-based approach. They found that BAG3 overexpression ameliorated tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits, likely through the enhancement of the autophagy-lysosome pathway.
First author Nicholas Sweeney, an Ohio State neuroscience research assistant, stated, “Our findings suggest that targeting neuronal BAG3 may be a promising therapeutic strategy for preventing or reducing Alzheimer’s disease-like pathology.”
This study builds on the researchers’ earlier work, which identified BAG3 as a hub gene controlling tau homeostasis from non-diseased human post-mortem tissue. Co-first author Tae Yeon Kim, a Ph.D. student of Ohio State’s Biomedical Sciences Graduate Program, added, “Given that previous research has shown that tau pathology increases after TBI, we hypothesized that BAG3 may be a contributing factor to tau accumulation after TBI.”
Future studies will focus on validating the relationship between TBI, BAG3, tau pathology, gliosis, and neurodegeneration using a new model of TBI called the Closed Head Induced Model of Engineered Rotational Acceleration (CHIMERA). This model mimics most common mild TBI conditions in humans.
According to Fu, “The completion of future studies will allow us to further understand the biological link between TBI and Alzheimer’s disease and develop novel therapies that can reduce the risk of developing Alzheimer’s after TBI.”
*Note:
1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
