A 1997 study indicated that Alzheimer's patients who carried one or both alleles that code for the E4 form of apolipoprotein had more severe neurodegeneration than did patients who carried only alleles coding for the E3 form of the protein. This and other evidence has led researchers to propose that ApoE4 makes the brain more susceptible to neurodegenerative diseases such Alzheimer's (as well as to poor outcome after acute insults such as head injury or stroke), while ApoE3, conversely, facilitates repair and regeneration. In the June 15 issue of Journal of Neuroscience, Manuel Buttini, Matthias Orth, Robert Mahley, and colleagues report results in ApoE knockout mice that support these proposals.

The ApoE knockout mice (Apoe[-/-]) lack any form of the gene for ApoE; several groups have reported that the mice suffer age-related neurodegeneration, but other groups failed to find such abnormalities. In this experiment, Buttini and colleagues did find age-related differences between Apoe[-/-] and wildtype mice. They found significantly lower levels of various neuronal markers (synaptophysin, MAP-2, phosphorylated neurofilaments) in the neocortex and/or hippocampus of ApoE[-/-] mice at seven to nine months.

Buttini and his colleagues then inserted genes coding for either human ApoE3 or ApoE4 into the embryos of ApoE[-/-] mice. They ensured that the genes would be expressed only in neurons by attaching them to the neuron-specific enolase promoter. The animals were then studied for resistance to the effects of aging and to exitotoxic CNS damage induced by systemic kainic acid.

The researchers found that mice expressing ApoE4 closely resembled the ApoE[-/-] mice at seven to nine months of age, with significantly lower levels of the neuronal markers in neocortex and in the hippocampus relative to wildtype controls. On the other hand, the mice expressing ApoE3 were spared the age-related degeneration. Similarly, ApoE3 conferred protection from the damage caused by kainic acid, but ApoE4 did not.—Hakon Heimer

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  1. . Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration. J Neurosci. 1999 Jun 15;19(12):4867-80. PubMed.