Tau Pathology, Metal Dyshomeostasis and Repetitive Mild Traumatic Brain Injury: An Unexplored Link Paving the Way for Neurodegeneration

Repetitive mild traumatic brain injury (r-mTBI), commonly experienced by athletes and military personnel, causes changes in multiple intracellular pathways, one of which involves the tau protein. Tau phosphorylation plays a role in several neurodegenerative conditions including chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder linked to repeated head trauma. There is now mounting evidence suggesting that tau phosphorylation may be regulated by metal ions (such as iron, zinc and copper), which themselves are implicated in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Recent work has also shown that a single TBI can result in age-dependent and region-specific modulation of metal ions. As such, this review explores the linkage among TBI, CTE, aging, and neurodegeneration, with a specific focus on the involvement of (and interaction between) tau pathology and metal dyshomeostasis. The authors highlight that metal dyshomeostasis has yet to be investigated in the context of repeat head trauma or CTE. Given the evidence that metal dyshomeostasis contributes to the onset and/or progression of neurodegeneration, and that CTE itself is a neurodegenerative condition, this brings to light an uncharted link that should be explored. The development of adequate models of r-mTBI and/or CTE will be crucial in deepening our understanding of the pathological mechanisms that drive the clinical manifestations in these conditions and also in the development of effective therapeutics targeted toward slowing progressive neurodegenerative disorders.