Susceptibility of transgenic mice expressing human apolipoprotein E to closed head injury: The allele E3 is neuroprotective whereas E4 increases fatalities

Apolipoprotein E, the major brain lipid-binding protein, is expressed in hu mans as three common isoforms (E2, E3 and E4). Previous studies revealed th at the allele apolipoprotein E4 is a major genetic risk factor of Alzheimer 's disease and that traumatic brain injury is associated with increased ris k for developing this disease. Furthermore, it has been suggested that the effects of traumatic head injury and apolipoprotein E4 in Alzheimer's disea se are synergistic. To test the hypothesis that the apolipoprotein E genoty pe affects susceptibility to brain injury, we subjected transgenic mice, ex pressing either human apolipoprotein E3 or human apolipoprotein E4 on a nul l mouse apolipoprotein E background and apolipoprotein E-deficient knockout s, to closed head injury and compared mortality, neurological recovery and the extent of brain damage of the survivors. More than 50% of the transgeni c mice expressing human apolipoprotein E4 died following closed head injury , whereas only half as many of the transgenic mice expressing human apolipo protein E3, and of the control and apolipoprotein E-deficient mice died dur ing this period (P < 0.02). A neurological severity score used for clinical assessment of the surviving mice up to 11 days after closed head injury re vealed that the four mouse groups displayed similar severity of damage at 1 h following injury. At three and 11 days post-injury, however, the neurolo gical severity scores of the transgenic mice expressing human apolipoprotei n E3 were significantly lower than those of the other three groups whose sc ores were similar, indicating better recovery of the transgenic mice expres sing human apolipoprotein E3. Histopathological examination of the mice per formed 11 days post-injury revealed, consistent with the above neurological results, that the size of the damaged brain area of the transgenic mice ex pressing human apolipoprotein E3 was smaller than that of the other head-in jured groups. These findings show that transgenic mice expressing human apolipoprotein E4 are more susceptible than those expressing apolipoprotein E3 to closed hea d injury. We suggest that this effect is due to both a protective effect of apolipoprotein E3 and an apolipoprotein E4-related pathological function. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.