Summary: A new study shows that traumatic brain injury (TBI) can raise the risk of Alzheimer’s disease by impairing the brain’s ability to clear damaged proteins, allowing toxic tau proteins to build up. The researchers identified decreased levels of BAG3, a protein that supports protein clearance via the autophagy-lysosome pathway, as a key factor in this process.
In mouse models, increasing BAG3 expression reduced tau accumulation and improved cognitive performance, pointing to BAG3 as a potential therapeutic target to lower Alzheimer’s risk following TBI. These findings clarify biological links between TBI and Alzheimer’s and suggest new directions for treatment development.
Key Facts:
- TBI disrupts protein clearance mechanisms and promotes accumulation of Alzheimer’s-like tau pathology.
- Levels of BAG3, a protein important for autophagy-lysosome mediated clearance, fall after TBI and are associated with cognitive impairment.
- Overexpressing BAG3 in neurons reduces tau pathology and improves synaptic and cognitive outcomes in experimental models.
Source: Ohio State University
Background: Each year, about 2.5 million people experience a traumatic brain injury (TBI). Epidemiological data indicate that TBI in early or mid-life increases the likelihood of later developing Alzheimer’s disease and related dementias. The molecular mechanisms that connect a past TBI to Alzheimer’s-like pathology, however, have remained unclear.
Researchers at The Ohio State University Wexner Medical Center and College of Medicine used controlled mouse models and analysis of human post-mortem brain tissue to investigate how TBI might trigger processes that resemble Alzheimer’s disease. Their results are published in the journal Acta Neuropathologica.
The study shows that a single, controlled cortical impact TBI increases levels of hyperphosphorylated tau, triggers astrocyte and microglial activation (gliosis), and produces synaptic dysfunction and measurable cognitive deficits in both wild-type and human tau knock-in mice. Similar pathological changes were identified in human brains with a history of TBI, and those changes were more pronounced in human cases with both Alzheimer’s disease and a history of TBI.
A central finding was the consistent downregulation of BAG3 after TBI. BAG3 (BCL2-associated athanogene 3) supports the autophagy-lysosome pathway, a cellular system that clears damaged or misfolded proteins. Reduced BAG3 correlated with lower levels of autophagy-lysosome pathway proteins and a buildup of hyperphosphorylated tau in neurons and oligodendrocytes. In vitro experiments confirmed that BAG3 knockdown impaired autophagic flux, while BAG3 overexpression enhanced it.
To test whether restoring BAG3 could counteract these effects, the team used an AAV-based method to overexpress BAG3 specifically in hippocampal neurons of mouse models. Neuronal BAG3 overexpression reduced tau hyperphosphorylation, ameliorated synaptic dysfunction, and improved cognitive performance. These benefits were associated with increased markers of autophagy-lysosome activity, suggesting that enhancing BAG3 helps restore protein clearance and limit tau accumulation after injury.
“Because both TBI and Alzheimer’s are common in the population, understanding the molecular steps that connect injury to neurodegeneration is essential for developing treatments that reduce long-term risk,” said study senior author Hongjun “Harry” Fu, PhD, assistant professor of neuroscience at Ohio State.
The study’s lead authors noted that previous work had already identified BAG3 as a central gene regulating tau homeostasis in non-diseased human brain tissue. This new research builds on that foundation by linking BAG3 dysfunction to the increased vulnerability of certain cells and regions to tau pathology after TBI.
“Our data indicate that BAG3 dysfunction disrupts protein clearance mechanisms and contributes directly to tau accumulation in both experimental models and human tissue from individuals with TBI,” said first author Nicholas Sweeney, a neuroscience research assistant at Ohio State. Co-first author Tae Yeon Kim, a PhD student, added that BAG3’s role could explain some of the cellular and regional susceptibility to Alzheimer’s-related tau pathology.
Future work will use a new closed-head TBI model—Closed Head Induced Model of Engineered Rotational Acceleration (CHIMERA)—that better replicates common human mild TBI scenarios. These studies aim to further validate the relationships among TBI, BAG3 signaling, tau pathology, gliosis, and neurodegeneration and to refine therapeutic strategies that could reduce Alzheimer’s risk after brain injury.
The research team included collaborators from Ohio State, Arizona, New York, West Virginia, and Japan.
Funding: This project received support from the Department of Defense, the National Institute on Aging of the National Institutes of Health, the Neurological Research Institute seed grant from The Ohio State University, and the Summer Undergraduate Research Fellowship from The Ohio State University Chronic Brain Injury Discovery Theme.
The authors report no conflicts of interest.
About this TBI and Alzheimer’s disease research news
Author: Eileen Scahill
Source: Ohio State University
Contact: Eileen Scahill – Ohio State University
Image: The image is credited to Neuroscience News
Original Research: Open access.
Title: Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway — Hongjun “Harry” Fu et al., Acta Neuropathologica
Abstract
Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway
Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer’s disease (AD) and AD-related dementia (ADRD). Yet the molecular pathways that drive TBI-induced AD-like pathology and cognitive decline are not fully understood.
In this study, a single controlled cortical impact TBI reduced BAG3 expression in neurons and oligodendrocytes and was associated with decreased proteins of the autophagy-lysosome pathway and increased accumulation of hyperphosphorylated tau in excitatory neurons and oligodendrocytes. These changes coincided with gliosis, synaptic dysfunction, and cognitive deficits in wild-type and human tau knock-in mice. Comparable pathological signatures were observed in human post-mortem tissue from individuals with TBI, and the effects were amplified in human AD cases with a history of TBI.
In vitro experiments showed that BAG3 knockdown impaired autophagic flux while BAG3 overexpression enhanced it. Targeted neuronal overexpression of BAG3 in the hippocampus of human tau knock-in mice mitigated AD-like pathology and cognitive deficits induced by TBI and increased markers related to the autophagy-lysosome pathway.
These results support the idea that enhancing neuronal BAG3 function might be a therapeutic strategy to prevent or reduce AD-like pathology and cognitive impairment that follow traumatic brain injury.