Role of misfolded tau in the onset and progression of brain toxicity after trauma

Abstract Background Traumatic brain injury (TBI) is associated with widespread tau pathology in about thirty percent of patients surviving late after injury. We previously found that TBI in mice induces a transmissible tau pathology (tau TBI ), with late cognitive decline and synaptic dysfunction. However, it is not clear whether tau TBI is a marker of ongoing neurodegeneration or a driver of functional decline. We employed the nematode C. elegans , which can recognize pathogenic forms of misfolded proteins, to investigate whether tau TBI is the primary toxic culprit in post-TBI neurodegeneration. Methods We developed an original approach involving the administration of brain homogenates from TBI mice to C. elegans , a valuable model for rapidly investigating the pathogenic effects of misfolded proteins in vivo . Brain homogenates from transgenic mice overexpressing tau P301L, a tauopathy mouse model, as well as pre-aggregated recombinant tau were employed to test whether abnormal tau conformers play a causal role in driving toxicity in TBI. Results Worms given brain homogenates from chronic but not acute TBI mice, or from mice in which tau TBI had been transmitted by intracerebral inoculation, had impaired motility and neuromuscular synaptic transmission. Results were similar when worms were exposed to brain homogenates from transgenic mice overexpressing tau P301L, a tauopathy mouse model, suggesting that TBI-induced and mutant tau have similar toxic properties. Harsh protease digestion to eliminate the protein component of the homogenates or pre-incubation with anti-tau antibodies abolished the toxicity. Homogenates of chronic TBI brains from tau knock-out mice were not toxic to C. elegans , whereas pre-aggregated recombinant tau was sufficient to impair their motility. Conclusions These results support a vital role of abnormal tau species in chronic neurodegeneration after TBI supporting the idea that targeting pathological tau may point to a therapeutic opportunity in trauma, and set the groundwork for the development of a C. elegans -based platform for screening anti-tau compounds.