Mechanics of Trauma-Induced Tauopathy

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Athletes and soldiers exposed to repeated head injuries have increased risk of developing chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by decreased cognitive function and tangled deposits of the protein tau in the brain. Though this correlation is well established, it is not known how the forces acting on the brain during injury cause development of CTE. This project will focus on understanding how mechanical stretching of neurons induces tau to be mislocalized to dendritic spines, where it alters the ability of neurons to receive electrochemical signals from other neurons. In addition, the project will study how the deformation of individual neurons during injury influences the likelihood of this mislocalization and loss of function. Brain injury and CTE affect millions of Americans every year, and it is likely that CTE cases will increase as soldiers exposed to improvised explosive devices in previous wars age. These studies will be first steps toward a mechanistic understanding of CTE initiation, and could provide important clues for better CTE treatment in the future. Recognizing that children of all ages can get brain injuries from falling off bikes or playing contact sports, the investigators have developed an outreach program aimed at teaching elementary school children about helmet design and head injury, which will be expanded as part of this award.This project has three research aims. The first will experimentally determine the mechanism through which stretching induces tau mislocalization, including focusing on microtubule rupture and focal swelling by rapidly stretching rat hippocampal neurons. The second will determine how cell structure and orientation relative to applied deformation influences tau mislocalization and subsequent loss of dendritic function. The final aim will develop a set of theoretical models to predict tauopathy based on neuron structure and the dynamics of brain tissue deformation, including a viscoelastic continuum model, a neurite model, and a cytoskeletal model.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.