Abstract
Traumatic brain injury (TBI) is characterized by acute neurological dysfunction and associated with the development of chronic traumatic encephalopathy (CTE) and Alzheimer’s disease. We previously showed that cis phosphorylated tau (cis P-tau), but not the trans form, contributes to tau pathology and functional impairment in an animal model of severe TBI. Here we found that in human samples obtained post TBI due to a variety of causes, cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Using mouse models of severe or repetitive TBI, we showed that cis P-tau elimination with a specific neutralizing antibody administered immediately or at delayed time points after injury, attenuates the development of neuropathology and brain dysfunction during acute and chronic phases including CTE-like pathology and dysfunction after repetitive TBI. Thus, cis P-tau contributes to short-term and long-term sequelae after TBI, but is effectively neutralized by cis antibody treatment.
Highlights
Traumatic brain injury (TBI) is characterized by acute neurological dysfunction and associated with the development of chronic traumatic encephalopathy (CTE) and Alzheimer’s disease
Neither cis nor trans Pro motif in tau (P-tau) was detected on controls or 1 h after TBI (Fig. 1a), as shown previously in normal human and mouse brains[48]
As documented by well-established antibodies, none of these acute TBI samples had obvious tau oligomers, early tau tangles (AT8 antibody), late tau tangles (AT100 antibody), amyloid beta peptide aggregation (Aβ antibody), or TDP-43 pathologies (TDP-43 antibody) in the cortex or hippocampus (Fig. 1e, f, Supplementary Table 1), in contrast to CTE and Alzheimer’s disease (AD) brains where cis P-tau partially co-localized with T22 and AT100 (Fig. 1g, h)
Summary
Traumatic brain injury (TBI) is characterized by acute neurological dysfunction and associated with the development of chronic traumatic encephalopathy (CTE) and Alzheimer’s disease. Within hours after closed head injury in mouse models, or following neuron stress in vitro, neurons produce cis P-tau prior to tau oligomerization and aggregation, which causes and spreads axonal pathology by a pathogenic process which we term cistauosis, including disruption of axonal microtubules and transport system, eventually leading to neuronal death[48]. Treating severe TBI mice with cis mAb eliminates early cis P-tau accumulation after injury and blocks cistauosis, and prevents the later development of tau tangles and brain atrophy[48] These results reveal that cis P-tau is critical for the development of axon pathologies, offering a potential link between TBI and neurodegeneration, and suggest cis P-tau antibody might be used to block tau pathology and prevent neurodegeneration after TBI48–50. The therapeutic potential of cis P-tau antibody is further supported by the findings that tau knockout prevents axon pathology and memory deficits after repetitive mild TBI in mice[52] and that immunotherapy can effectively remove toxic proteins in the brain, even in patients with mild cognitive impairment[27, 28, 53, 54]
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