In aggregate, these cellular and molecular changes further compromise neuronal function. Tangles in boxers with dementia pugilistica/CTE are structurally and chemically similar to those found in AD, in which CTE tangles also consist of hyperphosphorylated and ubiquitinated tau (Dale et al., 1991; Tokuda et al., 1991). Hyperphosphorylated tau from dementia pugilistica and AD brains is phosphorylated at the same amino acids, including the AT8 epitope, contains all six tau isoforms, and

shows the same relation between 3- and 4-repeat tau (Schmidt et al., 2001) (Figure 2). However, RG-7204 it should be noted that the tangles are found in different populations of cortical pyramidal neurons;

in dementia pugilistica/CTE, tangles are found in the superficial neocortical layers, while tangles in AD are found in deep and in superficial layers (Corsellis et al., 1973; Hof et al., 1992; McKee et al., 2009). Furthermore, tau pathology in CTE is patchy and irregularly distributed, possibly related to the many different directions of shearing forces induced by physical trauma (McKee et al., 2009). Experimental studies in animals suggest that intra-axonal tau accumulation and tau phosphorylation may be consequences of repeated brain trauma. selleck chemical Controlled brain trauma in animal models has been shown to increase tau immunoreactivity and tau phosphorylation in the perinuclear cytoplasm and in elongated

neuritis (Tran et al., 2011). These abnormalities correlate with injury severity (Tran et al., 2011). Studies on brain trauma induced by rotational acceleration in experimental animals show an accumulation of both tau and neurofilament proteins in damaged axons (Smith et al., 1999). Treatment with γ-secretase inhibitors mitigates amyloid pathology but does not affect TBI-induced whatever tangle formation, suggesting that TBI-induced tau pathology is not a downstream event of Aβ accumulation and plaque formation (Tran et al., 2011). The neurochemical disturbances that trigger tau pathology in CTE are not known in detail, but recent studies show that TBI induces an abnormal intra-axonal activation and accumulation in kinases that can phosphorylate tau (Tran et al., 2012). The kinase c-Jun N-terminal kinase (JNK) is markedly activated in damaged axons, and inhibition of JNK activity was found to reduce the accumulation of both total and phosphorylated tau in injured axons (Tran et al., 2012). After identification of Aβ as the key component of plaques in AD, Roberts et al. (1990) re-examined brains from the classic Corsellis report (Corsellis et al., 1973) to determine whether Aβ pathology may also be a key histopathological characteristic in dementia pugilistica.