Researchers found that traumatic brain injury increases synaptic dysfunction and cognitive impairment associated with the development of Alzheimer’s disease.
A recent study in Acta Neuropathologica investigated the relationship between tau protein and BCL2-associated athanogen 3 (BAG3) and its possible role in the pathology of traumatic brain injury (TBI).
Background
Traumatic brain injury is one of the leading causes of death and disability in the United States. There is increasing evidence that traumatic brain injury in young or middle age increases the risk of developing Alzheimer’s disease (AD) and related dementia (ADRD). However, the biological pathways behind TBI-induced Alzheimer’s disease-like disease and cognitive impairment are unknown.
Previous studies have shown that BAG3 modulates tau protein clearance. BAG3 enhances autophagy, which presumably reduces protein aggregation. Neuronal BAG3 deficiency exacerbates the accumulation of pathogenic tau proteins, while overexpression reduces tau formation.
In Alzheimer’s disease, BAG3 levels decrease in excitatory neurons, while they increase in astrocytes. BAG3 in astrocytes protects against alpha-synuclein and tau-related disorders. Thus, BAG3 regulates cellular susceptibility to tau-related pathology in Alzheimer’s disease.
About the study
The current study examined the involvement of BAG3 in TBI-related pathology, including tau phosphorylation, synaptic dysfunction, memory loss, and gliosis.
The researchers used wild-type and humanized tau-knockin (hTKI) mice for animal experiments. To confirm the pathological profiles of TBI in animal models, they examined the pathological profiles of postmortem brains from humans with or without a history of TBI. They obtained human brain tissue from the Banner Health Institute Brain Bank.
The control cases had the lowest National Institute on Aging-Alzheimer’s Association (NIA-AA) scores. TBI subjects without a confirmed AD diagnosis showed NIA-AA levels ranging from moderate to high. Patients with a confirmed AD diagnosis with or without TBI showed high NIA-AA scores. The scientists chose the inferior parietal lobe (IPL) of the human brain for research because it is one of the areas most affected by TBI.
Proteins isolated from the brains of mice and humans underwent immunofluorescence (IF) analysis. Because human fresh-frozen sections contain lipofuscin, an autofluorescent material that can distort IF findings, researchers suppressed autofluorescence using light-emitting diode (LED) arrays. Western blot (WB) assays evaluated the protein fractions produced by electrophoresis.
Researchers used human embryonic kidney 293 (HEK293) cells to investigate synaptic integrity after TBI and autophagy. Because synaptic disruption is linked to cognitive problems, they measured cognitive function. They induced TBI using controlled cortical impact (CCI). They performed behavioral assessments such as the Y maze, the open field test and the Morris water maze. The Y-maze test evaluated spatial working memory. The open field test measured changes in exploratory and locomotor activity.
The Morris Water Maze exam assessed spatial learning and memory. Furthermore, researchers investigated whether increasing BAG3 levels in neurons can reduce TBI-induced pathology and prevent synaptic dysfunction in hTKI mice. They overexpressed BAG3 in hippocampal neurons using stereotactic unilateral injections.
Results
TBI induced by cortical impact decreased BAG3 expression in oligodendrocytes (OLG) and excitatory neurons, resulting in the build-up of tau. In wild-type and hTKI animals, disrupting BAG3 homeostasis caused synaptic dysfunction, gliosis, and cognitive impairment. Reduced postsynaptic density protein 95 (PSD95) staining showed postsynaptic dysfunction. Mice performed poorly in the Y-maze test and showed altered performance in the open field test after traumatic brain injury, in line with synaptic results.
BAG3 knockdown drastically reduced autophagic flux, but overexpression significantly enhanced it in the in vitro institutions. Overexpression of BAG3 in hippocampal cells reduced AD-like pathologies and cognitive impairment induced by traumatic brain injury in hTKI mice by stimulating the autophagy-lysosome pathway (ALP).
BAG3 levels increased in astrocytes expressing glial fibrillary acidic protein (GFAP). The results suggest that astrocytes may upregulate BAG3 as a compensatory strategy to defend themselves against tau accumulation or to help clear tau aggregates.
The number of GFAP-positive astrocytes and ionized calcium-binding adapter molecule 1 (IBA1)-positive microglia increased as PHF1+ tau pathology progressed. The data suggest that astrocytes and microglia increase in areas of tau disease.
Inverse correlations between BAG3 and PHF1 expression show that cells with phosphorylated tau accumulation had much lower BAG3 levels than cells without. Thus, BAG3 loss could lead to build-up of tau protein in oligodendrocytes after TBI or AD.
Overexpressing neuronal BAG3 may reduce the burden of tau buildup and alleviate memory problems after traumatic brain injury. BAG3 overexpression also improved ALP efficiency in vivo. However, neuronal overexpression of BAG3 alone cannot reduce the gliosis observed after traumatic brain injury. The team found identical changes in human TBI cases and exaggerated findings in human AD cases with TBI.
Conclusion
The study found that TBI affects BAG3 expression in neurons, oligodendrocytes and astrocytes, making cells less or more sensitive to tau buildup after TBI. BAG3 inhibits tau phosphorylation, synaptic disruption and cognitive impairment caused by TBI via modulating the ALP pathway.
The results indicate that targeting neuronal BAG3 may be a therapeutic strategy to prevent or reduce AD-like cognitive and pathological changes caused by TBI.