, 1990). The intensity of Aβ plaque deposition was comparable to that found in AD cases (Roberts et al., 1990). The presence of Aβ plaques after acute severe brain trauma was verified in many reports, including studies on fresh surgically excised brain tissue samples (Roberts et al., 1994; Ikonomovic et al., 2004). Aggregation of Aβ and plaque formation constitutes central elements of AD. Aβ is generated from amyloid precursor protein (APP) by the concerted action of β-secretase and γ-secretase (Blennow et al., 2006). β-Secretase was identified as β-site

APP-cleaving enzyme 1 (BACE1), while γ-secretase consists of a complex with four components that include presenilin, nicastrin, Pen-2, and Aph-1. Presenilin is present in the active site of the γ-secretase complex (Blennow et al., 2006). selleck Expression of APP is highest in neurons and, under normal conditions, APP (Koo et al., 1990; Ferreira et al., 1993; Kamal et al., 2000), β-secretase (BACE1) and γ-secretase (presenilin) (Sheng et al., 2003) are translocated by axonal transport to the synapses, where APP can be cleaved by the secretases, thus generating Aβ (Kamal et al., 2001). Extensive research contends that APP has neurotrophic functions, including promotion of axonal sprouting, neurite outgrowth, and synaptogenesis, www.selleckchem.com/products/Adriamycin.html which are important for neuronal survival after axonal damage (Small,

1998; Small et al., 1999; Alvarez et al., 1992; Xie et al., 2003). second APP is upregulated in response to brain trauma and administration of soluble α-secretase-cleaved APP improves functional outcome and reduces neuronal cell loss and axonal injury after experimental TBI in animals (Thornton et al., 2006). Studies on human brain tissue samples have demonstrated that APP accumulates in neurons and axons after brain trauma with axonal damage (McKenzie et al., 1994; Sherriff et al., 1994; Gentleman et al., 1995; Ahlgren et al., 1996; Gleckman et al., 1999). Postmortem studies on human brain tissue samples from patients who sustained mild TBI but died of other causes have shown that

this APP accumulation occurs very rapidly (within a few hours) after brain trauma and is present in cases with mild trauma (Blumbergs et al., 1994; McKenzie et al., 1996; Johnson et al., 2012). Besides APP, acute intra-axonal Aβ accumulation is a prevalent trait in human TBI (Smith et al., 2003; Uryu et al., 2007; Chen et al., 2009). Release of β-amyloid (especially Aβ42) into tissue and plaque formation around damaged axons occurs after APP accumulation and β-amyloid production in damaged axons (Roberts et al., 1991; Graham et al., 1995; Horsburgh et al., 2000a; Smith et al., 2003). Studies on brain trauma induced by rotational acceleration in animal experiments show an accumulation of APP and Aβ within damaged axons throughout the white matter, which in a subset of animals is accompanied by Aβ diffuse plaques (Smith et al.