Subacute to chronic Alzheimer-like alterations after controlled cortical impact in human tau transgenic mice

Yanchong Zhang,Feng Wu,Cheng-Xin Gong,Fei Liu,Wen Hu,Khalid Iqbal

doi:10.1038/s41598-019-40678-4

Abstract

Repetitive traumatic brain injury (TBI) has been linked to late life development of chronic traumatic encephalopathy (CTE), a neurodegenerative disorder histopathologically characterized by perivascular tangles of hyperphosphorylated tau at the depth of sulci to later widespread neurofibrillary pathology. Although tau hyperphosphorylation and neurofibrillary-like pathology have been observed in the brain of transgenic mice overexpressing human tau with aggregation-prone mutation after TBI, they have not been consistently recapitulated in rodents expressing wild-type tau only. Here, we characterized Alzheimer-like alterations behaviorally, biochemically and immunohistochemically 6 weeks and 7 months after unilateral mild-to-moderate controlled cortical impact (CCI) in 5–7-month-old Tg/htau mice, which express all six isoforms of non-mutated human tau in a mouse tau null background. We detected hyperphosphorylation of tau at multiple sites in ipsilateral hippocampus 6 weeks but not 7 months after CCI. However, neuronal accumulation of AT8 positive phospho-tau was sustained in the chronic phase, in parallel to prolonged astrogliosis, and decreased neural and synaptic markers. The mice with CCI also exhibited cognitive and locomotor impairment. These results indicate subacute to chronic Alzheimer-like alterations after CCI in Tg/htau mice. This is the first known study providing insight into the role of CCI in Alzheimer-like brain alterations in young adult mice expressing only non-mutated human tau.

Highlights

Head trauma is the leading cause of death and disability in children and adults from 1 to 44 years of age; traumatic brain injury (TBI) represents the major type of trauma which leads to morbidity, disability and mortality[1]
We found that cortical impact (CCI) and sham mice traveled comparable total distance on the elevated plus maze (Fig. 2A), and exhibited similar probability to enter the open arms, with no statistical difference in the number of entries and total time spent in the open arms between the two groups (Fig. 2B,C)
We found that CCI and sham mice traveled a similar total distance, showed similar entries into and similar time spent in the central area (Fig. 2D–F)

Summary

Introduction

Head trauma is the leading cause of death and disability in children and adults from 1 to 44 years of age; traumatic brain injury (TBI) represents the major type of trauma which leads to morbidity, disability and mortality[1]. Chronic traumatic encephalopathy (CTE) has been known for many years to be present in many individuals exposed to repetitive, often mild or concussive head injury as in boxers and American football players[14,15,16,17,18,19]; whereas a recent study has shown widespread tau and amyloid-β pathologies, the two hallmarks of AD, many years after a single TBI in humans[20]. Tau hyperphosphorylation and tau pathology after TBI have been observed using transgenic mice overexpressing human tau with aggregation-prone mutation[34], they have not been consistently and assuredly recapitulated in rodents expressing wild-type tau only[35,36,37,38]. It remains to be characterized whether and to what extent tau hyperphosphorylation and filamentous tau pathology can be mimicked in young adult mice which express relatively physiological level of non-mutated human tau

Methods

Results

Conclusion