Neurofilament compaction is an early event caused by calpain-mediated proteolysis of neurofilament side arms or phosphorylation. Calcium influx triggers microtubule disassembly (Giza and Hovda, 2001; Barkhoudarian et al., 2011). Cytoskeletal pathology may have several mediators. In animal trauma models of axonal pathology,

calcium homeostasis disruption results in calpain-mediated Ku-0059436 concentration proteolytic degradation of essential cytoskeletal proteins, such as neurofilament proteins. Calcium homeostasis is the primary regulator of calpain activation; disruption leads to increased intracellular-free calcium (McCracken et al., 1999; McGinn et al., 2009; Saatman et al., 2010). Microtubule disorganization may be a direct effect of dynamic axon stretching. Ultrastructural analysis of axons displays immediate

breakage and buckling of microtubules postinjury, which triggers progressive microtubule disassembly (Tang-Schomer et al., 2010). This results in accumulation of organelles that are transported in the axon, and axonal swelling called axonal retraction balls, with eventual disconnection and axotomy (Giza and Hovda, 2001; Barkhoudarian et al., 2011). Neuronal damage with axonal bulbs and swellings is most commonly located in the cortical sulci at the interface between gray and white matter (Chen et al., 2004). MRI studies that use DTI show that the extent of DAI after mild TBI is related to postconcussion cognitive problems (Lipton et al., 2008; Niogi et al., 2008; Wilde et al., 2008). Protein Tyrosine Kinase inhibitor As early as the 1970s, Corsellis et al. (1973) reported neurofibrillary tangles in neocortical areas in boxers with CTE. Several studies have since confirmed these findings of extensive tangle pathology in postmortem studies (Dale et al., 1991; Tokuda et al., 1991; Schmidt et al., 2001; Hof et al., 1992; Geddes et al., 1996). In addition to neurofibrillary tangles, neuropil treads and glial tangles are also elements of CTE (McKee et al., 2009). Cortical tangles also constitute a key component of Alzheimer’s disease. But because they are found in many

only chronic neurological diseases (Wisniewski et al., 1979) with different etiology, it is possible that they represent a more general response to neurodegenerative pathology. Indeed, their abundance in CTE, which is caused by repeated brain trauma episodes, further supports that they may represent a response to brain damage. Tangles are found intracellularly in the cytoplasm of neurons and consist of thread-like aggregates of hyperphosphorylated tau protein (Grundke-Iqbal et al., 1986). Tau is a normal axonal protein that binds to microtubules via its microtubule-binding domains, thus promoting microtubule assembly and stability. There are six different isoforms of tau, each containing several serine or threonine residues that can be phosphorylated. In AD, tau is frequently found in a hyperphosphorylated form (Figure 2).