Susceptibility of transgenic mice expressing human apolipoprotein E to closed head injury: The allele E3 is neuroprotective whereas E4 increases fatalities
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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Permanent address: Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona, Israel.
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The first two authors contributed equally to this work.