B. Mahley (Abstract 303) reported new data on transgenic mice that could help elucidate the role of ApoE isoforms in neurodegeneration. He began his lecture with an overview of the structure and function of apolipoprotein E (ApoE), a lipid transport protein that exhibits an isoform-specific association with the risk of AD (the E4 isoform being linked to greater risk). Much is known about the structure of ApoE, which includes an N-terminal portion that contains the receptor binding domain (residues 136-150) and a C-terminal portion that includes the major lipid-binding region (residues 244-272). Studies designed to uncover isoform-specific differences in ApoE function suggest that the arginine at position 61 is more available for interaction with the C-terminal region (glutamic acid at position 255) in E4 as compared to the E2 and E3 isoforms. This suggests the possibility of somehow modifying this interaction to make the E4 isoform function more like the E3 isoform.
Regarding the function of different isoforms, early studies demonstrated isoform-specific effects of ApoE on neurite outgrowth such that the E3 isoform promotes outgrowth whereas the E4 isoform inhibits outgrowth, leading to the hypothesis that E4 may not provide effective neuronal repair or protection. As a test of this hypothesis, transgenic mice were generated in which human E3 or E4 are expressed under the control of the NSE (neuron-specific enolase) promoter in ApoE knockout mice (ApoE -/-). The level of ApoE in the brains of the transgenic mice is comparable to that in the human brain. The mice were evaluated in terms of neuronal and behavioral changes. Synaptophysin and MAP-2 immunoreactivity are reduced in ApoE -/- mice and in E4 transgenic mice as compared with wild-type or E3 transgenic mice (more pronounced declines at seven to nine months than at three to four months). A similar result is obtained with kainic acid injections, which elicit greater reduction of these neuronal markers in the ApoE -/- and E4 transgenic lines.
Behavioral analysis included water maze performance and measures of exploratory activity. For these studies analysis was restricted to six-month-old female mice, which showed greater effects than male mice or younger female mice. Again, the same general group pattern was obtained as for the immunohistochemical studies; wild-type and E3 mice showed similar performance levels but ApoE -/- and E4 mice showed deficits. Decreases in exploratory behavior were due to declines in vertical motion (rearing events). Interestingly, on the water maze task, the E4 mice showed greater deficits than the ApoE -/- mice. There were no deficits in any of the mouse lines in visual or motor skills.
Dr. Mahley concluded that ApoE -/- and E4 transgenic mice have greater "neurodegeneration," although no direct evidence for degeneration of neurons (as opposed to altered development of these markers) was provided in this presentation. These mouse lines may prove useful in ultimately clarifying the normal function of ApoE in brain as well as its potential role in neurodegenerative diseases.—Keith A. Crutcher
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