Elsevier

Neuroscience

Volume 101, Issue 4, 30 November 2000, Pages 879-884
Neuroscience

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

https://doi.org/10.1016/S0306-4522(00)00438-3Get rights and content

Abstract

Apolipoprotein E, the major brain lipid-binding protein, is expressed in humans as three common isoforms (E2, E3 and E4). Previous studies revealed that the allele apolipoprotein E4 is a major genetic risk factor of Alzheimer’s disease and that traumatic brain injury is associated with increased risk for developing this disease. Furthermore, it has been suggested that the effects of traumatic head injury and apolipoprotein E4 in Alzheimer’s disease are synergistic. To test the hypothesis that the apolipoprotein E genotype affects susceptibility to brain injury, we subjected transgenic mice, expressing either human apolipoprotein E3 or human apolipoprotein E4 on a null mouse apolipoprotein E background and apolipoprotein E-deficient knockouts, to closed head injury and compared mortality, neurological recovery and the extent of brain damage of the survivors. More than 50% of the transgenic mice expressing human apolipoprotein E4 died following closed head injury, whereas only half as many of the transgenic mice expressing human apolipoprotein E3, and of the control and apolipoprotein E-deficient mice died during 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 revealed that the four mouse groups displayed similar severity of damage at 1 h following injury. At three and 11 days post-injury, however, the neurological severity scores of the transgenic mice expressing human apolipoprotein E3 were significantly lower than those of the other three groups whose scores were similar, indicating better recovery of the transgenic mice expressing human apolipoprotein E3. Histopathological examination of the mice performed 11 days post-injury revealed, consistent with the above neurological results, that the size of the damaged brain area of the transgenic mice expressing human apolipoprotein E3 was smaller than that of the other head-injured groups.

These findings show that transgenic mice expressing human apolipoprotein E4 are more susceptible than those expressing apolipoprotein E3 to closed head injury. We suggest that this effect is due to both a protective effect of apolipoprotein E3 and an apolipoprotein E4-related pathological function.

Section snippets

Animals

Human apoE3 and apoE4 transgenic mice were generated on an apoE-deficient C57BL/6J background utilizing human apoE3 and apoE4 transgenic constructs as previously reported.53 Accordingly, cosmid libraries were constructed from lymphoblasts of humans known to be homozygous carriers for apoE3 or apoE4, after which fragments containing human regulatory sequences and the coding sequences for human apoE were used to produce the transgenic mice. The experiments were performed with the apoE3-453 and

Results

The susceptibilities of the apoE3 and apoE4 transgenic mice and of apoE-deficient and normal control mice to CHI were assessed by measurements of their neurological status during 11 days following head injury and by monitoring the number of mice that died in each group.

As shown in Table 2, four control, six apoE-deficient and five apoE3 transgenic mice died within 11 days following CHI, which translates approximately to the same percentage of the total mice for each of these groups (i.e. 27%,

Discussion

This study revealed that mice transgenic for human apoE4 are more susceptible to CHI than human apoE3 transgenic mice. Furthermore, neurological and histological analysis revealed that the apoE3 transgenic mice recovered more rapidly from CHI than control, apoE-deficient and apoE4 transgenic mice and that the infarct size of the injured apoE3 mice was significantly smaller than that of the other mouse groups. In contrast, analysis of the fatalities following CHI revealed that a similar fraction

Conclusions

This study has revealed that human apoE3 transgenic mice are less susceptible than human apoE4 transgenic mice to CHI and that this effect is due both to increased vulnerability of the apoE4 transgenic mice, manifested in increased fatality, and to more effective recovery of the apoE3 mice.

Acknowledgements

We thank Duke University and Glaxo Wellcome for kindly providing the transgenic mice. This work was supported partly by grants from the Joint German and Israeli Research Projects sponsored by the German and Israeli Ministries of Science (grant no. 1626), from the Harry Stern National Center for Alzheimer’s Disease and Related Disorders, from the Jo and Inez Eichenbaum Foundation and from the Revah-Kabelli Fund. D.M. Michaelson is the incumbent of the Myriam Lebach Chair in Molecular

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  • Cited by (0)

    Permanent address: Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona, Israel.

    The first two authors contributed equally to this work.

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