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Tau oligomers from traumatic brain injury (TBI) were associated with accelerated cognitive decline and pathologic seeding in a mouse model, suggesting the importance of their role in TBI.1
“Scientists have identified altered, dysfunctional tau as a factor in the memory loss and other symptoms associated with both Alzheimer’s disease and TBI. These results suggest that the increased risk for development of neurodegenerative diseases later in life after TBI may be dependent on the presence of toxic tau. Tau oligomers therefore may represent a good target for the prevention and treatment of these disorders,” wrote Rakez Kayed, PhD, of the Mitchell Center for Neurodegenerative Diseases at the University of Texas Medical Branch in Galveston, in an email to Neurology Advisor.
According to the paper published in the Journal of Neurotrauma, each year there are approximately 1.5 million instances of TBI, which is a risk factor for dementia. A proposed mechanism of neuronal injury after TBI involves accumulation of tau oligomers, a toxic form of tau proteins. The authors note that early damage from misfolding of tau monomers may be involved in Alzheimer’s disease independent of the neurofibrillary tangles.
Dr Kayed and colleagues isolated the protein from a mouse model with induced TBI in order to understand the impact of the tau oligomers. They injected purified tau oligomers into the brains of cognitively normal mice to observe the pathology and development of cognitive impairment. Mice with blast-induced TBI were found to have high levels of tau oligomers in the hippocampus, with significantly higher levels observed with immunofluorescent staining (P=.0217).
Further, cognitively normal mice with hippocampal injections of tau oligomers performed significantly worse on spontaneous alternation for a spatial memory task (P=.0091). Likewise, mice with hippocampal injections of tau oligomer were found to have increased levels within the cerebellum, “suggesting that tau oligomers may be responsible for seeding the spread of pathology following TBI.”
Neuroblastoma cells treated with isolated tau oligomers demonstrated evidence of less cell viability (P=.0005). Conversely, when isolated tau oligomers were pretreated with a tau oligomer monoclonal antibody, the toxic effects were attenuated and cell viability did not seem to be altered.
Dr Kayed continued in the email, “Our findings revealed that the mice injected with tau oligomers from traumatic brain injury developed memory loss and that the molecules spread throughout the animals’ brains. Therefore, independent of other factors that cause acute TBI symptoms, tau oligomers may increase risk of neurodegenerative disease later in life. These findings add to growing evidence that tau oligomers, rather than larger neurofibrillary tangles, are the most toxic form of tau in disease and that multiple different forms of TBI in rodents initiate the formation of these toxic structures.”
The authors write, “these data suggest that the increased prevalence of acquiring [Alzheimer’s disease] many years after the occurrence of TBI may be due to the seeding and spread of tau oligomers released following neuronal injury.”
The study was funded by the Cullen Trust, the Alzheimer’s Drug Discovery Foundation, the Mitchell Center for Neurodegenerative Disease, and the Sealy Center for Vaccine Development. Dr Kayed reported having patent applications involving tau oligomers and antibodies.
