Stabilizing microtubules increases acute cellular injury at high strain rates

Mechanical strain is a key contributor to mild traumatic brain injury (mTBI), yet the impact of varying strain magnitudes and strain rates on cellular function and disease remain poorly understood. In this study, we examined acute membrane damage responses to mechanical strain in SH-SY5Y cells and the modulatory roles of Tau phosphorylation and microtubule stability in the context of mTBI. Using a custom cell-stretching system, we found that increased MT stability, induced by paclitaxel, increases acute membrane damage, while MT depolymerization via nocodazole reduces it. Interestingly, overexpression of wild-type Tau exacerbates injury under strain. Pharmacological treatments with phosphatase and kinase inhibitors that are used as therapeutics for neurological disorders further revealed that Tau phosphorylation modulates mTBI outcomes, highlighting a complex interplay between Tau modification and microtubule stability. These findings advance our understanding of neuronal mechanobiology and suggest potential therapeutic targets for mitigating TBI-induced damage.