Tau Oligomers Derived from Traumatic Brain Injury Cause Cognitive Impairment and Accelerate Onset of Pathology in Htau Mice

Abstract

Tau aggregation is a pathological feature of numerous neurodegenerative disorders and has also been shown to occur under certain conditions of traumatic brain injury (TBI). Currently, no effective treatments exist for the long-term effects of TBI. In some cases, TBI not only induces cognitive changes immediately post-injury, but also leads to increased incidence of neurodegeneration later in life. Growing evidence from our lab and others suggests that the oligomeric forms of tau initiate the onset and spread of neurodegenerative tauopathies. Previously, we have shown increased levels of brainderived tau oligomers in autopsy samples from patients diagnosed with Alzheimer's disease. We have also shown similar increases in tau oligomers in animal models of neurodegenerative diseases and TBI. In the current study, we evaluated the presence of tau oligomers in blast-induced TBI. To test the direct impact of TBI-derived tau oligomer toxicity, we isolated tau oligomers from brains of rats that underwent either a blast-or a fluid percussion injury-induced TBI. Oligomers were characterized biochemically and morphologically and were then injected into hippocampi of mice overexpressing human tau (Htau). Mice were cognitively evaluated and brains were collected for immunological analysis after testing. We found that tau oligomers form as a result of brain injury in two different models of TBI. Additionally, these oligomers accelerated onset of cognitive deficits when injected into brains of Htau mice. Tau oligomer levels increased in the hippocampal injection sites and cerebellum, suggesting that tau oligomers may be responsible for seeding the spread of pathology post-TBI. Our results suggest that tau oligomers play an important role in the toxicity underlying TBI and may be a viable therapeutic target.

Role of Tau Acetylation in Alzheimer’s Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment

“…Kondo and colleagues proposed that cis tau might play a role [27]. Kayed et al assert that it is more likely the tau oligomers [28]. We however have discovered an earlier contributor to the disease process in tau acetylation.…”

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

“…Once tau is secreted, the extracellular tau has the ability to enhance tau pathology. For example, transplanting TBI induced tau oligomers into naive brains of hTau transgenic mice results in oligomeric spread of tau and accelerated cognitive impairment (Gerson et al , 2016), secreted tau fibrils are capable of inducing transcellular misfolding and tau aggregation (Kfoury et al , 2012), and hyperphosphorylated tau is capable of forming filaments and tangles with non-phosphorylated tau (Alonso et al , 1996). Therefore, it is possible that in non-familial tauopathies, such as CTE, an initial event, such as repetitive TBI, triggers a misfolding cascade which can then be transmitted in a prion-like manner (Morales et al , 2015).…”

“…CCI, a focal model of injury which includes aspects of contusion, hemorrhage and diffuse injury (Hall et al , 2005), results in severity-dependent increases in cleaved tau (c-tau), with severe injury inducing significant increases in c-tau beginning at 6h in the cortex and 48h in the hippocampus, increases which are sustained for at least seven days following injury and which are attenuated by the neuroprotective drug CsA (Gabbita et al , 2005). Similarly, following a moderate FPI, a mixed model of focal and diffuse injury (Thompson et al , 2005), oligomeric and phosphorylated tau are increased acutely: 4h, 24h and 2 weeks post-injury (Gerson et al , 2016; Hawkins et al , 2013). Mild blast TBI, which encompasses both the blast wave and rotational acceleration-deceleration forces and results in diffuse injury, transient axonal injury, and vascular pathology (Courtney and Courtney, 2015; Kovacs et al , 2014), has also been shown to increase tau acutely following injury.…”

“…Seventy days following a single blast injury in rats, total tau protein is also increased in several brain regions including the amygdala, prefrontal cortex and hippocampus; an affect which can be attenuated by environmental enrichment (Kovesdi et al , 2011). Tau oligomers have also been observed to develop one month following a single blast TBI (Gerson et al , 2016). In fact, tau oligomers extracted from rat brains one month following a single blast TBI have prion-like characteristics, increasing the spread of tau pathology and accelerating the rate of cognitive decline when injected into brains of transgenic mice overexpressing human tau (Gerson et al , 2016).…”

“…Tau oligomers have also been observed to develop one month following a single blast TBI (Gerson et al , 2016). In fact, tau oligomers extracted from rat brains one month following a single blast TBI have prion-like characteristics, increasing the spread of tau pathology and accelerating the rate of cognitive decline when injected into brains of transgenic mice overexpressing human tau (Gerson et al , 2016). Tau aggregation also occurs following blast TBI, although in a delayed manner.…”