Neuropharmacology

Objectives: 

Traumatic brain injury (TBI) is one of the major risk factor for Alzheimer’s disease (AD), whose pathological hallmarks include tau hyperphosphorylation. However, so far tauopathy has been undetectable acutely after TBI and how TBI leads to tauopathy which in turn would increase risk of AD remains unknown. We herein identify a neurotoxic cis conformation of phosphorylated tau at Thr231 as a major early driver of tauopathy and neurodegeneration that is effectively blocked by the conformation specific monoclonal antibody. 

 

Methods: 

We immunostained control and human TBI brains with our cis/trans monoclonal antibodies. Also, we examined TBI mouse models treated with either control IgG or cis mAb employing immunostaining and electron microscopy. Moreover, we studied risk-taking behaviour of those TBI mice. 

 

Results: 

We found robust cis p-tau after sport- and military-related TBI in humans and mice. Acutely after TBI in mice, neurons prominently produce cis p-tau, which disrupts axonal microtubule network, spreads to other neurons, and leads to apoptosis, a pathogenic process, which we termed “cistauosis” that appears long before known tauopathy. Also, while TBI causes abnormal risk-taking behaviour in mouse models, cis antibody treatment restores the phenomena. 

 

Conclusions: 

Treating TBI mice with cis antibody prevents tauopathy development and spread, and restores brain histopathological and functional outcomes. These results uncover cistausosis as an early driver of tauopathy and neurodegeneration upon TBI. We anticipate that cis p-tau will be a new early biomarker and that cis p-tau antibody may be used to treat or even prevent TBI, chronic traumatic encephalopathy and AD.