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

Studies have shown that individuals with both a history of traumatic brain injury and inheritance of apolipoprotein E-4 (ApoE4) allele are associated with a poor neurologic outcome and an increased risk for Alzheimer's disease. We assessed the hypothesis that thrombin released during brain injury causes an increase in apolipoprotein-E levels and such increase in the levels of apolipoprotein-E4 isoform may have amyloidogenic effects. Rats received either thrombin (100 nm, 0.25 microl/hr, 28 days) or vehicle via intracerebroventricular (i.c.v.) infusion. Thrombin treatment increased apolipoprotein-E levels in hippocampus as compared to vehicle treatment (P < 0.001). Infusion of human apolipoprotein-E4 (0.6 ng/hr, i.c.v., 56 days) into rats resulted in beta-amyloid deposition and increased the number of GFAP-positive astrocytes. ApoE4 infusion also resulted in significant spatial memory deficits. These findings suggest that thrombin released during brain injury may contribute to an increase in apolipoprotein-E levels. Such increase in Apolipoprotein-E4 isoform facilitates beta-amyloid deposition and cognitive deficits.