Each year, approximately 2.5 million people suffer from traumatic brain injuries (TBI), which can increase the risk of developing Alzheimer’s disease later in life. Researchers from The Ohio State University Wexner Medical Center and College of Medicine conducted a study using mouse models and human post-mortem brain tissue to investigate the molecular mechanisms that may lead to an increased risk of Alzheimer’s following TBI. The study, led by Hongjun “Harry” Fu, PhD, assistant professor of neuroscience at Ohio State, aimed to better understand the transition from TBI to Alzheimer’s in order to develop potential therapies to reduce this risk. The findings are published in the journal Acta Neuropathologica.
The researchers discovered that following a TBI, there is an increase in hyperphosphorylated tau, astro- and microgliosis, synaptic dysfunction, and cognitive impairments that are associated with the development of Alzheimer’s disease. Additionally, 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 brain tissue. Through overexpressing BAG3 in neurons, they were able to ameliorate tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits, potentially by enhancing the autophagy-lysosome pathway. The researchers believe that targeting neuronal BAG3 may be a therapeutic strategy to prevent or reduce Alzheimer’s disease-like pathology.
This study builds on previous research that identified BAG3 as a key gene controlling tau homeostasis in non-diseased human post-mortem tissue. Co-first author Tae Yeon Kim, a PhD student at Ohio State, suggested that BAG3 may play a role in the vulnerability to tau pathology in Alzheimer’s disease. The researchers found that BAG3 dysfunction contributes to the disruption of protein clearance mechanisms, leading to tau accumulation in both mouse models and human brain tissue with a history of TBI and Alzheimer’s. Future research will focus on validating the relationship between TBI, BAG3, tau pathology, gliosis, and neurodegeneration using a new model of TBI known as the Closed Head Induced Model of Engineered Rotational Acceleration (CHIMERA) to further understand the biological link between TBI and Alzheimer’s.
The research team, which included scientists from multiple institutions in the United States and Japan, received support from various sources including the Department of Defense, the National Institute on Aging of the National Institutes of Health, the Neurological Research Institute seed grant from Ohio State University, and the Summer Undergraduate Research Fellowship from Ohio State University Chronic Brain Injury Discovery Theme. The authors have disclosed no conflicts of interest. By continuing to investigate the relationship between TBI and Alzheimer’s, the researchers aim to develop novel therapies that can reduce the risk of developing Alzheimer’s following a traumatic brain injury.