Human Brain Contusions Contain Pathogenic Transmissible Species that Induce Progressive Cognitive Decline and Tau...

Area of Science:

• Neuroscience
• Neuropathology
• Molecular Biology

Background:

• Traumatic brain injury (TBI) is a known risk factor for dementia.
• The mechanisms linking TBI to dementia are not fully understood.
• Previous studies showed TBI induces prion-like tau pathology in mice.

Purpose of the Study:

• To investigate if severe TBI in humans generates self-propagating tau conformers.
• To determine if human TBI-induced tau pathology can spread in a mouse model.
• To explore the role of endogenous tau in TBI-related pathology.

Main Methods:

• Biochemical analysis of tau and phosphorylated tau (P-tau) in human TBI brain samples.
• Inoculation studies using human TBI homogenates in wild-type (WT) and tau knockout (KO) mice.
• Assessment of cognitive function and neuropathological changes in inoculated mice.

Main Results:

• Human TBI homogenates induced widespread tau deposition and cognitive deficits in WT mice.
• Pathological changes included hippocampal synaptic loss and altered gene expression.
• The effects were tau-dependent, as KO mice showed no significant pathology.

Conclusions:

• Severe TBI in humans generates transmissible tau conformers (tau^TBI) acutely after injury.
• These tau^TBI conformers may worsen post-traumatic pathology.
• This process could contribute to an increased risk of dementia following TBI.