University of Tasmania, Australia

TBI involves shear and torsional forces on axons that instigate a series of secondary intracellular changes that can result in axonal swelling, breakage and disconnection of CNS pathways, a process known as diffuse axonal injury (DAI). In this study we are utilizing a number of animal and cell culture techniques to investigate the effect of a traumatic injury. Our in vivo techniques model both acute injury as well as a more diffuse central fluid percussion injury model in transgenic animals to determine the role of specific proteins in the subsequent development of pathology. Furthermore we have developed a novel in vitro model that induces transient (approximately 20-50 ms) stretching of axon bundles (Chung et al., 2005). Using this model we have demonstrated how alterations in specific cytoskeletal proteins and intra-axonal calcium dynamics contribute to the evolving secondary axonopathy of DAI following acute stretch injury. In this regard, the dissolution of microtubules and the accumulation of neurofilaments (NFs, neuronal intermediate filaments) leading to axonal swelling appear to play critical roles in DAI. Our studies seek to determine whether neuronal intermediate filaments changes are a critical component of the sequence of cellular changes that leads to axonal injury. The transgenic mouse colonies used in these studies include a mouse genetic model where the NF ‘light’ gene has been knocked out (NFL KO) resulting in significantly diminished content of neuronal intermediate filaments and a Alzheimer’s disease mouse model of amyloidosis. These studies will determine the role of TBI in the development of AD pathology, potential key role of NFs in nerve cell biology and in the response of neurons to injury.