Development and spread of tau pathology after TBI

Abstract

Traumatic brain injury (TBI) is a risk factor for delayed neurodegeneration and dementia. We recently found that TBI in wild-type (WT) mice induces a self-propagating phosphorylated (P)-tau pathology that progressively spreads in the brain and can be horizontally transmitted to naïve mice by intracerebral inoculation, causing synaptic degeneration and memory deficits (Zanier et al., 2018). This observation indicates that experimental TBI generates pathogenic tau prions. The aim of this study was to test whether pathogenic tau prions were generated in human TBI. P-tau pathology was investigated in brain autopsies or biopsies of human TBI by immunohistochemistry and biochemical analysis. The emergence of tau prions was tested by inoculating human TBI brain homogenates into the brain of naïve WT (C57BL/6J) mice. We found that single moderate/severe TBI is associated with the emergence of widespread tau pathology in a proportion of humans surviving late after injury with a specific pattern of distribution. In a proof of principle study, we found memory deficits accompanied by P-tau pathology and synaptic loss in WT mice receiving a brain homogenate prepared from a human TBI specimen. Secondary transmission studies are ongoing and indicate memory deficits in the inoculated mice as early as 4 months post-inoculation. These data indicate tau prion formation in human TBI, suggesting that self-sustained propagation of tau pathology may be responsible for delayed neurodegeneration, cognitive decline and dementia.