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

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.