Chemo-Mechanical Regulation of Tau Phosphorylation Following Traumatic Brain Injuries

Abstract Traumatic brain injuries are characterized by damage to axonal cytoskeletal proteins. Here, we present a mathematical model predicting the chemo-mechanical disruption of intra-axonal micro-tubule assembly in terms of hyperphosphorylation-led dysfunction of tubulin-binding tau proteins. Intracellular calcium accumulation following a trauma leads to calpain activation, disturbing the downstream kinase-phosphatase activity balance which causes tau hyperphosphorylation. We develop a computational framework, using finite element methods, predicting the spatiotemporal evolution of mechanical stress and ensuing tau hyperphosphorylation in the human brain after traumatic brain injury-inducing loads. We compare our predictions with previously reported experimental and clinical observations to validate the model. Our model provides important insights into the secondary effects of traumatic brain injuries and can be essential in their clinical management.