TY - JOUR
T1 - Apolipoprotein E4 decreases whereas apolipoprotein E3 increases the level of secreted amyloid precursor protein after closed head injury
AU - Ezra, Y.
AU - Oron, L.
AU - Moskovich, L.
AU - Roses, A. D.
AU - Beni, S. M.
AU - Shohami, E.
AU - Michaelson, D. M.
N1 - Funding Information:
We thank Duke University and Glaxo Wellcome for kindly providing the transgenic mice, and Drs. Joseph Buxbaum and Tobias Hartmann for generously providing us with mAb 3129 and antibody 22/13. This work was supported in part by grants to D.M.M. from the European Community (grant 2001/00972), from the Fund for Basic Research of the Israel Academy of Science and Humanities (grant 43/00-1); from the Harry Stern National Center for Alzheimer's Disease and Related Disorders, and from the Jo and Inez Eichenbaum Foundation. D.M.M. is the incumbent of the Myriam Lebach Chair in Molecular Neurodegeneration. E.S. is affiliated with the David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem.
PY - 2003/10/6
Y1 - 2003/10/6
N2 - 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-β, 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 α-cleavage of APP (APPsα) were then determined 24 h following injury. Immunoblotting revealed no significant differences between the basal APP, APPs and APPsα 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 APPsα 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.
AB - 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-β, 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 α-cleavage of APP (APPsα) were then determined 24 h following injury. Immunoblotting revealed no significant differences between the basal APP, APPs and APPsα 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 APPsα 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.
KW - Amyloid precursor protein
KW - Apolipoprotein E
KW - Apolipoprotein E transgenic mice
KW - Head trauma
UR - http://www.scopus.com/inward/record.url?scp=0141756277&partnerID=8YFLogxK
U2 - 10.1016/S0306-4522(03)00436-6
DO - 10.1016/S0306-4522(03)00436-6
M3 - Article
C2 - 14521991
AN - SCOPUS:0141756277
SN - 0306-4522
VL - 121
SP - 315
EP - 325
JO - Neuroscience
JF - Neuroscience
IS - 2
ER -