- Apolipoprotein E (apoE4) and head trauma are important genetic and environmental risk factors for Alzheimer's disease. Furthermore, apoE4 increases both the acute and chronic consequences of head trauma. The latter are associated with the deposition of amyloid-beta, which is particularly elevated in apoE4 subjects. The short-term effects of head injury are associated with transiently increased metabolism of amyloid precursor protein (APP) and its secreted fragment, APPs. In the present study, we examined the possibility that the acute, short-term pathological effects of apoE4 following head trauma and the corresponding neuroprotective effects of apoE3 are related to isoform-specific effects of apoE on APP metabolism. Accordingly, male transgenic mice expressing human apoE3 or apoE4 on a null mouse apoE background and apoE-deficient and control mice were subjected to closed head injury (CHI). The resulting effects on brain APP, and on its secreted products, APPs and secreted product of the alpha-cleavage of APP (APPsalpha) were then determined 24 h following injury. Immunoblotting revealed no significant differences between the basal APP, APPs and APPsalpha levels of the hippocampus or the cortex of the control and the apoE3 and ApoE4 transgenic mice. The apoE-deficient mice also had similar cortical basal levels of APP and its metabolites, whereas their corresponding basal hippocampal APP and APPs levels were lower than those of the other groups. CHI lowered the hipppocampal APPs and APPsalpha levels of the apoE4 transgenic mice, whereas those of the apoE3 transgenic mice and of the control and apoE-deficient mice were not affected by this insult. In contrast, CHI raised the cortical APP and APPs levels of the apoE3 transgenic mice but had no significant effect on those of the other mice groups. These animal model findings suggest that the acute, short-term pathological effects of apoE4 following CHI and the corresponding neuroprotective effects of apoE3 may be mediated by their opposing effects on the expression and cleavage of cortical and hippocampal APP. Similar isoform-specific interactions between apoE and APP may play a role in the acute, short-term effects of head trauma in humans.