. ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory. Neurobiol Dis. 2003 Aug;13(3):273-82. PubMed.

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  1. Levi et al. conducted an interesting study on the influence of the two human ApoE isoforms E3 and E4 on behavior and neurochemistry of mice. As science often does, this paper raises new questions and points to new aspects. The first thing you learn from the study is that human ApoE may be bad for mice. Control mice harboring their endogenous mouse ApoE gene met the given criteria of learning tasks after only five days. In contrast, transgenic human ApoE3 and E4 animals, both generated on a mouse ApoE-knockout background, needed 17 days when housed in standard cages, i.e., under impoverished environmental stimulation.

    Unfortunately, the authors gave no information about the level of ApoE in wild-type mice with mouse ApoE, and transgenic mice with human ApoE alone. So the difference in ApoE levels may account for this difference in the learning procedure, not the difference in ApoE structure. If, however, the protein levels were comparable, then the data touches on a general problem of transgenic animals. The fact that human ApoE exists and functions in the mouse metabolism, with mouse ApoE receptors and other ApoE-interacting mouse molecules, would raise the theoretical possibility that the differences observed may result from inappropriate interaction of human ApoE with mouse metabolism. In human, where putative interaction partners of ApoE are of the same species, effects of ApoE isoforms may be quite different from those observed in the transgenic mice.

    A second thing you may learn from the study relates to the role of environment in learning and memory. The given information suggests that ApoE3 and ApoE4 protein expression levels were comparable in the mice (at least under basal, i.e., untrained conditions). Therefore, the better performance of ApoE3 mice living in an enriched enviroment compared to “enriched” E4 mice seems at first glance to depend on differences in ApoE molecule rather than in protein levels. However, ApoE levels were not determined before and after the learning tasks. It just might be that regulation of ApoE is different in ApoE4-producing animals than in E3 animals. And if synaptic plasticity, which is more likely to be challenged in an enriched environment, is indeed modulated by ApoE, then slight differences in ApoE levels may play a more important role in plasticity-related changes, for example, by supplying different amounts of cholesterol. Also, one cannot rule out that the difference between ApoE3 and 4 may result from a difference in the random gene integration during genetic engineering. Such a different integration locus may exhibit an overt difference in the phenotype only under conditions of an enriched environment. A different transgenic strain, having most likely a different gene integration site, would rule out this possibility.

  2. Reply to Thomas Ohm:
    We agree with Dr. Ohm's comments regarding the conceptual difficulties of comparing the effects of an endogenous molecule to that of an analogous transgenic molecule from another species. However, since the levels of expression of the human ApoE3 and ApoE4 transgenic molecules in our study were similar before and after environmental stimulation (see Figure 10 of Levi et al., 2003, we think that comparison of the physiological and biochemical effects of these molecules is valid and not hampered by the above considerations.

    References:

    . ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory. Neurobiol Dis. 2003 Aug;13(3):273-82. PubMed.