Elsevier

Neurobiology of Disease

Volume 8, Issue 4, August 2001, Pages 611-625
Neurobiology of Disease

Regular Article
Impaired Neuronal Plasticity in Transgenic Mice Expressing Human Apolipoprotein E4 Compared to E3 in a Model of Entorhinal Cortex Lesion

https://doi.org/10.1006/nbdi.2001.0401Get rights and content

Abstract

The apolipoprotein E (APOE) ϵ4 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 (ϵ3 and ϵ4). 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 ϵ3 mice compared to APOE ϵ4 mice. By day 90 post-ECL compensatory sprouting and reactive synaptogenesis had taken place in the dentate gyrus of APOE ϵ3 mice such that GAP-43 and synaptophysin immunoreactivity had returned to prelesion levels. In contrast, APOE ϵ4 mice displayed significant deficits in synaptophysin and GAP-43 immunostaining compared to the APOE ϵ3 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 ϵ3 mice had increased by 45% but only 20% in APOE ϵ4 mice (P < 0.0001). ApoE immunoreactivity was increased within the neuropil and glia to the same extent in APOE ϵ3 and APOE ϵ4 mice post-ECL. There was no significant difference in the deposition and clearance of degeneration products between APOE ϵ3 and ϵ4 mice post-ECL. These results indicate that neuronal plasticity is impaired in transgenic mice possessing human APOE ϵ4 alleles compared to APOE ϵ3. These isoform-specific differences in plasticity may relate to the severity of AD and poor, long-term recovery after head injury in APOE ϵ4 individuals.

References (64)

  • D.M. Holtzman et al.

    Potential role of ApoE in structural plasticity in the nervous system. Implications for disorders of the central nervous system

    Trends Cardiovasc. Med.

    (1998)
  • K. Horsburgh et al.

    The role of apolipoprotein E in Alzheimer's disease, acute brain injury, and cerebrovascular disease: Evidence of common mechanisms and utility of animal models

    Neurobiol. Aging

    (2000)
  • C. Jolivalt et al.

    Differential oxidation of apolipoprotein E isoforms and interaction with phospholipids

    Free Rad. Biol. Med.

    (2000)
  • E. Kida et al.

    Deposition of apolipoproteins E and J in senile plaques is topographically determined in both Alzheimer's disease and down's syndrome brain

    Brain Res.

    (1995)
  • E. Masliah et al.

    Neurodegeneration in the central nervous system of ApoE deficient mice

    Exp. Neurol.

    (1995)
  • E. Masliah et al.

    Patterns of aberrant sprouting in Alzheimer's disease

    Neuron

    (1991)
  • E. Masliah et al.

    Alterations in apolipoprotein E expression during ageing and neurodegeneration

    Prog. Neurobiol.

    (1996)
  • B.P. Nathan et al.

    The inhibitory effect of apolipoprotein E4 on neurite outgrowth is associated with microtubule depolymerisation

    J. Biol. Chem.

    (1995)
  • J. Poirier et al.

    Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats

    Neuroscience

    (1993)
  • J. Poirier et al.

    Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning

    Mol. Brain Res.

    (1991)
  • B.L. Scott et al.

    Human apolipoprotein E accelerates microtubule polymerisation in vitro

    Neurosci. Lett.

    (1998)
  • D.J. Stone et al.

    Astrocytes and microglia respond to estrogen with increased ApoE mRNA in vivo and in vitro

    Exp. Neurol.

    (1997)
  • G.M. Teasdale et al.

    Association of apolipoprotein E polymorphism with outcome after head injury

    Lancet

    (1997)
  • L. Terrisse et al.

    Modulation of apolipoprotein D and apolipoprotein E expression in rat hippocampus after entorhinal cortex lesion

    Mol. Brain Res.

    (1999)
  • I. Tesseur et al.

    Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice

    Am. J. Pathol.

    (2000)
  • P. Xu et al.

    Regionally specific neuronal expression of human APOE gene in transgenic mice

    Neurosci. Lett.

    (1998)
  • P. Xu et al.

    Human apolipoprotein E2, E3 and E4 isoform-specific transgenic mice: Human-like pattern of glial and neuronal immunoreactivity in the central nervous system not observed in wild-type mice

    Neurobiol. Disease

    (1996)
  • T. Arendt et al.

    Plastic neuronal remodelling is impaired in patients with Alzheimer's disease carrying apolipoprotein ϵ4 allele

    J. Neurosci.

    (1997)
  • J.K. Boyles et al.

    Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system

    J. Clin. Invest.

    (1985)
  • M. Buttini et al.

    Expression of human apolipoprotein E3 or E4 in the brains of Apo−/− mice: Isoform specific effects on neurodegeneration

    J. Neurosci.

    (1999)
  • J. Corey-Bloom et al.

    E4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer's disease

    Neurology

    (2000)
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