Chronic thrombin exposure results in an increase in apolipoprotein-E levels.

A major genetic risk factor for sporadic Alzheimer’s disease is inheritance of the epsilon-4 allele of apolipoprotein E (Corder et al., 1993; Poirier et al., 1993a; Rebeck et al., 1993; Saunders et al., 1993; Crutcher, 2004). ApoE-4 is also associated with an earlier age of onset of the disease (Corder et al., 1993) and an increased amyloid plaque burden (Mortimer et al., 1991; Schemechel et al., 1993; Sadowski et al., 2004). There is significant evidence suggesting that the interactions between apoE and Aβ are critical for the development of Aβ deposits (Strittmatter et al., 1993). Apolipoprotein-E (ApoE) is a 34-kDa lipoprotein synthesized within the CNS that regulates plasma lipid transport and clearance. It is involved in nerve regeneration after injury (Mahley, 1988; Boyles et al., 1989; LeBlanc and Poduslo, 1990). Traumatic brain injury (e.g., hemorrhagic stroke, head injury), wherein neurons are exposed to high thrombin levels, is a significant risk factor for AD (Mayeaux et al., 1995). Moreover, this risk increases several times in individuals possessing the ApoE-4 allele relative to people inheriting ApoE-2 and ApoE-3 alleles (Mortimer et al., 1991; Mayeaux et al., 1995; Teasdale et al., 1997). Also, AD risk is significantly greater in ApoE-4 carriers, who have experienced head trauma than in those without a history of head trauma (Kutner et al., 2000). The E4 iso-form is also associated with neurologic deficits in the survivors of traumatic brain injury (Wisniewski et al., 1994; Teasdale et al., 1997; Friedman, 1999) and is a negative risk factor for recovery from head trauma (Friedman et al., 1999; Graham et al., 1999, 2000; Kutner et al., 2000). Aged football players possessing ApoE-4 iso-form have shown significantly lower cognitive performance than E2- or E3-carriers (Kutner et al., 2000). These observations suggest a significant interaction between traumatic brain injury and ApoE4 allele. We observed previously that chronic exposure to thrombin, which is released at a high concentration after hemorrhagic stroke or traumatic brain injury, produces significant cognitive deficits that can be prevented by direct and specific inhibition of thrombin by hirudin (Mhatre et al., 2004) or thrombin receptor (PAR-1) antagonist (unpublished observations). Thrombin-induced cognitive deficits were associated with ventricular enlargement, increased number of reactive glial fibrillary acidic protein-positive astrocytes and TUNEL-positive cells, and alterations in the phosphorylation state of cytoskeletal proteins suggesting neuronal injury (Mhatre et al., 2004). Emmerling et al. (2000) observed previously that the levels of Aβ1–42 increase in a positive correlation with apolipoprotein-E levels in the cerebrospinal fluid of patients after severe brain injury. Despite the positive correlation between apolipoprotein-E and Aβ1–42 levels observed in these patients, it is not yet clear whether the increase in apolipoprotein-E levels after brain injury in ApoE4-carriers contributes to Aβ deposition. The present study is designed to determine whether chronic exposure to thrombin as observed after brain injury alters apolipoprotein-E levels and whether such alterations in apolipoprotein-E levels in ApoE4-carriers contribute to β-amyloid deposition.