Impaired neuronal plasticity in transgenic mice expressing human apolipoprotein E4 compared to E3 in a model of entorhinal cortex lesion

The apolipoprotein E (APOE) epsilon4 allele is a major risk factor for late-onset familial and sporadic Alzheimer's disease (AD) and is associated with a poor outcome after brain injury. Each apoE isoform is suggested to have differential effects on neuronal repair mechanisms within the CNS. In the present study, APOE genotype influence on the immediate response to injury and subsequent repair process was examined in a line of transgenic APOE mice possessing human APOE gene insertions [epsilon3 and epsilon4). Quantification of synaptophysin and GAP-43 immunoreactivity was used to measure the extent of degeneration and regeneration after entorhinal cortex lesion (ECL). Progressive neurodegenerative decline occurred in the ipsilateral dentate gyrus until day 28 post-ECL which was more severe in APOE epsilon3 mice compared to APOE epsilon4 mice. By day 90 post-ECL compensatory sprouting and reactive synaptogenesis had taken place in the dentate gyrus of APOE epsilon3 mice such that GAP-43 and synaptophysin immunoreactivity had returned to prelesion levels. In contrast, APOE epsilon4 mice displayed significant deficits in synaptophysin and GAP-43 immunostaining compared to the APOE epsilon3 mice (P < 0.05). Expansion of the inner molecular layer (IML) was used as a measure of the sprouting index from the commissural-associational pathway and by day 90 post-ECL the IML width in APOE epsilon3 mice had increased by 45% but only 20% in APOE epsilon4 mice (P < 0.0001). ApoE immunoreactivity was increased within the neuropil and glia to the same extent in APOE epsilon3 and APOE epsilon4 mice post-ECL. There was no significant difference in the deposition and clearance of degeneration products between APOE epsilon3 and epsilon4 mice post-ECL. These results indicate that neuronal plasticity is impaired in transgenic mice possessing human APOE epsilon4 alleles compared to APOE epsilon3. These isoform-specific differences in plasticity may relate to the severity of AD and poor, long-term recovery after head injury in APOE epsilon4 individuals. (C) 2001 Academic Press.