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

T. Sabo, L. Lomnitski, A. Nyska, S. Beni, R. R. Maronpot, E. Shohami, A. D. Roses, D. M. Michaelson

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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 1h 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. Copyright (C) 2000 IBRO.

Original languageEnglish
Pages (from-to)879-884
Number of pages6
JournalNeuroscience
Volume101
Issue number4
DOIs
StatePublished - 30 Nov 2000
Externally publishedYes

Bibliographical note

Funding Information:
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 Neurodegeneration. E. Shohami is affiliated with the David R. Bloom Center for Pharmacy in the Hebrew University School of Pharmacy.

Keywords

  • Alzheimer's disease
  • Animal models
  • Apolipoprotein E3
  • Apolipoprotein E4

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