Summary: A study has found that traumatic brain injury ( TBI ) increases the risk of Alzheimer’s disease by disrupting protein clearance, leading to the accumulation of toxic tau proteins in the brain. Scientists discovered that TBI downregulates BAG3, a protein important for clearing broken molecules, which contributes to Alzheimer ‘s-related beta formation.
In rat models, BAG3 overexpression reduced tau accumulation and improved mental function, which suggests a potential medical target. These findings open the door to developing treatments that could lower Alzheimer’s risk following TBI, providing new insights into the natural connection between TBI and Alzheimer’s.
Important Information:
- TBI disrupts protein clearance, leading to Alzheimer ‘s-like tau accumulation.
- Downregulation of BAG3 amino after TBI contributes to brain difficulties.
- BAG3 expression speeds up mental development and improves model mental performance.
Origin: Ohio State University
Each year, about 2.5 million people suffer from traumatic brain injuries ( TBI ), which often increases their risk for developing Alzheimer’s disease later in life.
Scientists led by , The Ohio State University Wexner Medical Center , and , College of Medicine , used rat models and people post-mortem brain cells to study the molecular underpinnings that may increase the risk of Alzheimer’s after TBI.
” Because of the prevalence of both TBI and Alzheimer’s in people, understanding the chemical mechanism that supports the transition from Ba to Alzheimer’s is vital to developing potential solutions that reduce this risk”, said study senior author , Hongjun” Harry” Fu, PhD, associate professor of , neuroscience , at Ohio State.
Study studies are published online in the journal , Acta Neuropathologica.
Scientists found that TBI raises hyperphosphorylated tau, astro- and microgliosis, neural function and mental impairments linked to developing Alzheimer’s disease.
Additionally, they discovered that the downregulation of BAG3, a protein involved in protein certification through the autophagy-lysosome road, causes the formation of hyperphosphorylated beta in cells and oligodendrocytes following TBI in both animal post-mortem brain cells and mouse models with TBI histories.
Using an AAV-based view of overexpressing BAG3 in neurons, they found that BAG3 overexpression ameliorates tau hyperphosphorylation, neural difficulties, and cognitive deficits, possible through the development of the autophagy-lysosome road.
” Based on our observations, we believe that targeting cerebral BAG3 may be a medical plan for preventing or reducing Alzheimer’s disease-like pathology”, said review first author Nicholas Sweeney, an Ohio State science research associate.
This work builds on earlier studies that demonstrated that non-diseased individual post-mortem tissue’s BAG3 gateway gene controls tau equilibrium. Thus, BAG3 may be a contributing factor to the biological and regional risk to protein disease in AD, according to co-first writer Tae Yeon Kim, a PhD student at Ohio State’s Graduate Program in Biomedical Sciences.
We were curious if BAG3 may be a factor in the increase in tau pathology after TBI because previous research using human tissue and mouse models showed that tau pathology increases after TBI.
In fact, we discovered that BAG3 dysfunction contributes to the breakdown of protein clearance mechanisms that cause tau accumulation in human post-mortem tissue and in mouse models affected by TBI and Alzheimer’s.
Using a new TBI model, research will attempt to validate the association between TBI, BAG3, tau pathology, gliosis, and neurodegeneration. The Closed Head Induced Model of Engineered Rotational Acceleration ( CHIMERA ), or” Closed Head Induced Model of Engineered Rotational Acceleration,” mimics most common mild TBI symptoms in people, Fu said.
Future research will help us better understand how TBI and Alzheimer’s are related biologically, and create novel treatments that can lower the risk of Alzheimer’s disease following a TBI, Fu said.
The research team included scientists from Ohio State, Arizona, New York, West Virginia and Japan.
Funding: This work was supported by the Department of Defense, the National Institute on Aging of the National Institutes of Health, the Ohio State University’s Neurological Research Institute seed grant, and the Ohio State University’s Chronic Brain Injury Discovery Theme.
The authors disclose 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.
” Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway” by 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 ). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear.
In this study, we found that a single TBI ( induced by controlled cortical impact ) reduced the expression of BCL2-associated athanogene 3 ( BAG3 ) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway ( ALP ) and increased hyperphosphorylated tau ( ptau ) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type ( WT ) and human tau knock-in (hTKI ) mice.
These pathological changes were also found in human cases with TBI histories and exaggerated in human AD cases with TBI.
Autophagic flux was significantly impacted by BAG3 knockdown, while BAG3 overexpression significantly increased it in vitro. A specific overexpression of neuronal BAG3 in the hippocampus reduced AD-like pathology and cognitive deficits in hTKI mice, which are related to increased ALP-related proteins.
Our research suggests that utilizing neuronal BAG3 as a therapeutic approach to preventing or reducing AD-like pathology and cognitive deficits brought on by TBI.
