TRAUMATIC brain injury (TBI) accounts for 30% of all injury-related deaths in the United States, and is a major cause of death and disability in the country. New research has emerged that puts a spotlight on the connection between TBI and Alzheimer’s disease (AD). While increasing evidence suggests that sustaining a TBI in early or middle life significantly raises the risk of developing Alzheimer’s disease and related dementias, the biological mechanisms are unclear.
A research team led by Nicholas Sweeney, Ohio State University, Columbus, used a controlled cortical impact model to investigate these mechanisms. The study authors found that a single TBI event led to a reduced expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes. This reduction was correlated with impaired autophagy-lysosome pathway, which resulted in a significant accumulation of hyperphosphorylated tau protein (ptau) in excitatory neurons and oligodendrocytes. These molecular changes contribute to gliosis, synaptic dysfunction, and cognitive deficits in both wild-type and human tau knock-in (hTKI) mice.
Similar changes were observed in humans with a history of TBI, particularly among those who later developed Alzheimer’s. The study demonstrated that reducing BAG3 hindered the brain’s ability to clear out tau proteins, while boosting BAG3 levels enhanced this process. Notably, when BAG3 was overexpressed in the hippocampus of specific mouse models, researchers observed improvements in cognitive function and reductions in Alzheimer’s-like symptoms.
These findings suggest that targeting neuronal BAG3 could be a promising strategy for preventing or mitigating Alzheimer’s-like pathology and cognitive deficits resulting from TBI. As researchers continue to explore these molecular pathways, there is hope for developing effective interventions for patients at risk of Alzheimer’s following traumatic brain injuries.
Reference: Sweeney N et al. Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway. Acta Neuropathol. 2024;148(52).
Anaya Malik | AMJ
