Human Brain Contusions Contain Pathogenic Transmissible Species that Induce Progressive Cognitive Decline and Tau Pathology in Mice

Abstract

Objective: Traumatic brain injury (TBI) is an established risk factor for dementia, although the underlying mechanisms remain unclear. Our previous research demonstrated that a single severe TBI in wild-type (WT) mice induces a prion-like form of tau (tau^TBI) that spreads throughout the brain, leading to memory deficits. Here, we investigated whether similar self-propagating tau^TBI conformers are generated in humans after severe TBI.

Methods: We biochemically assessed tau and phosphorylated tau (P-tau) levels in human brain contusions surgically removed acutely after severe TBI. Inoculation studies were performed using human TBI brain homogenates in WT and tau knockout (KO) mice to investigate the role of endogenous tau in tau^TBI propagation. Cognitive function was evaluated using the novel object recognition test, the radial arm water maze, and the Y-maze. Pathological changes in the brain of the inoculated mice were analyzed by histological and biochemical analyses, and targeted transcriptomics.

Results: Inoculation of human TBI brain homogenates in WT mice caused widespread tau deposition and cognitive impairment, hippocampal synaptic loss, and disease-associated transcriptomic changes. Effects were similar upon secondary inoculation in WT but not tau KO mice, confirming a tau-dependent mechanism.

Interpretation: Severe TBI induces transmissible tau^TBI conformers in humans acutely after injury, potentially exacerbating post-traumatic pathology, and increasing the risk for dementia later in life. ANN NEUROL 2025.