# Targeting dual specificity tyrosine-phosphorylation-regulated kinase 1A mitigates tauopathy and enhances recovery after repetitive head injury

## TL;DR

Inhibiting a specific brain enzyme helps reduce brain damage and improve recovery after head injuries.

## Contribution

This study shows that inhibiting DYRK1A reduces tau pathology and neuroinflammation after repetitive brain injuries.

## Key findings

- DYRK1A inhibition reduces phosphorylated Tau accumulation in brain regions after injury.
- Treatment improves motor performance and reduces glial activation in injured mice.
- SM07883 shows therapeutic potential for long-term TBI consequences.

## Abstract

Chronic neuroinflammation and accumulation of phosphorylated Tau (pTau) are hallmark features of several neurodegenerative diseases and are also observed in some individuals who have sustained traumatic brain injury (TBI). Notably, more than 70 % of patients presenting to emergency departments with mild TBI (Glasgow Coma Score of 13–15) exhibit neuropathological alterations despite a normal sensorium, and up to half experience prolonged post-injury symptoms. Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a serine/threonine protein kinase that contributes to tau phosphorylation and regulates immune responses. Inhibition of DYRK1A may therefore attenuate both tau pathology and neuroinflammation following injury. Transgenic mice expressing human Tau (hTau) were subjected to repetitive head injury (RHI) over a 3-month period and treated with either vehicle or SM07883, a potent, brain-penetrant DYRK1A inhibitor. Behavioral performance was evaluated using the Rotarod and Barnes Maze tests, and neuropathological assessments were performed six months after the first injury. SM07883 treatment restored locomotor performance in injured animals and ameliorated age-related motor decline in sham-treated mice. These behavioral improvements were accompanied by significant reductions in RHI-induced pTau accumulation within the midbrain and brainstem, along with decreased astroglial and microglial activation in the corpus callosum, brainstem, and cortical regions beneath the injury site. Collectively, these findings demonstrate that DYRK1A inhibition mitigates tau pathology and chronic neuroinflammation following repetitive injury, supporting DYRK1A as a promising therapeutic target for the long-term neurological consequences of TBI.

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