The Influence of APOE Genotype on Neuronal Plasticity: Implications for Alzheimer's Disease and Recovery After Head Injury

White, Fiona (2001) The Influence of APOE Genotype on Neuronal Plasticity: Implications for Alzheimer's Disease and Recovery After Head Injury. PhD thesis, University of Glasgow.

Abstract

Apolipoprotein E (APOE: gene, apoE: protein) is a lipid transport protein which has a well-characterised role in response to peripheral nerve injury. It has been demonstrated that the APOE epsilon4 allele of the gene is a major risk factor for Alzheimer's disease and is associated with a poor outcome after brain injury. The mechanisms underlying this are unclear but may involve a role for apoE in neuronal repair processes. This thesis investigated the role of apoE in repair processes after brain injury and determined whether this effect was APOE genotype dependent. In order to address this, models of synaptic plasticity (in vitro and in vivo) were validated. Using these models the role of apoE could be defined. The influence of APOE genotype was determined using two different lines (human promoter and GFAP promoter) of genetically modified mice (APOE knockout, human epsilon3 and epsilon4 alleles). The main studies and results are as follows: (1) Investigation of ApoE in Relation to Degeneration/ Regeneration Using a Mouse Model of Entorhinal Cortex Lesion An in vivo model of hippocampal plasticity was characterised in C57BL/6J mice (the background strain of genetically modified mice used in this thesis). A lesion of the entorhinal cortex (ECL) was induced by stereotactic injection of ibotenic acid. Specific markers (synaptophysin, GAP-43 and MAP-2) were used to define the temporal profile of degeneration and regeneration post-ECL. In the molecular layers of the dentate gyrus, synaptic decline and fibre degeneration occurred up to 28 days post-ECL, but at 90 days post-ECL, synaptogenesis and fibre sprouting were observed. Alterations in apoE paralleled degeneration and regeneration post-ECL. ApoE was upregulated within the neuropil and reactive astrocytes at day 7 post-ECL, with a further increase in the neuropil of the outer molecular layer at day 90 post- ECL. This pattern of upregulation was similar to alterations observed for apoJ. There were minimal alterations in LRP (apoE receptor) with an increase in LRP immunoreactivity on reactive astrocytes at day 7 post-ECL. Degeneration products identified by silver staining were maximal 3 days post-ECL and absent by day 90 post-ECL. This study demonstrated the utility of the entorhinal cortex lesion as a reproducible model of hippocampal plasticity. The results also supported a role for apoE in neuronal repair processes after brain injury. (2) Analysis of APOE Genotype Influence on CNS Plasticity in Transgenic Mice Expressing Human APOE epsilon3 and epsilon4 Alleles (under a human promoter sequence) Following Entorhinal Cortex Lesion The entorhinal cortex was lesioned in APOE transgenic mice, which express human APOE alleles (epsilon3, epsilon4) in astrocytes and neurons. This study assessed APOE genotype influence on the long-term response to brain injury. Specific markers (synaptophysin, GAP-43 and MAP-2) were used to define the temporal profile of degeneration and regeneration post-ECL. Initially APOEepsilon3 mice exhibited more extensive degeneration than epsilon4 mice. However, with longer recovery the APOEepsilonA mice demonstrated an impaired reparative capacity. There were no significant differences in the extent of apoE, apoJ and LRP immunoreactivity between APOEs3 and e4 mice. There was also no significant difference in the deposition and clearance of degeneration products between APOEepsilon3 and epsilon4 mice. APOEepsilon4 mice displayed a deficit in MAP-2 immunoreactivity compared to APOEepsilon3 mice that paralleled the deficit in reparative capacity. The dendrites in the molecular layer of APOEepsilon4 mice were disorganised and disarrayed. This study indicated that the epsilon4 allele was associated with impaired neuronal repair. The underlying mechanism may involve apoE isoform differences in interactions with cytoskeletal proteins. (3) Analysis of APOE Genotype Influence on CNS Plasticity in APOE Knockouts and Transgenic Mice Expressing Human APOEepsilon3 and epsilon4 Alleles (GFAP Promoter) Following Entorhinal Cortex Lesion The entorhinal cortex was lesioned in APOE knockout, epsilon3 and epsilon4 transgenic mice (expressing human APOE in astrocytes) and the influence of APOE genotype on the long-term response to brain injury was assessed. In this study it was shown that mice expressing the APOEepsilon4 allele displayed impaired neuronal sprouting capabilities compared to APOE knockout and epsilon3 mice, however there was no difference in synaptic density between APOE knockout, epsilon3 and epsilon4 mice at any time-point. Alterations in apoE and apoJ paralleled regeneration but there was no significant difference between APOE epsilon3 and epsilon4 mice. Similarly, there were no significant differences in alterations in LRP, MAPs or extent of degeneration product clearance. This study indicated that neuronal repair mechanisms were impaired in APOEepsilon4 mice compared to APOE knockout and epsilon3 mice. There were no significant differences in dendritic structure unlike that shown in the previous transgenic line and this suggests that the underlying mechanisms may not be directly related to cytoskeletal interactions in this particular line of transgenic (astrocytic expression). (Abstract shortened by ProQuest.).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Karen Horsburgh
• Keywords: Neurosciences
• Date of Award: 2001
• Depositing User: Enlighten Team
• Unique ID: glathesis:2001-75727
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 18:30
• Last Modified: 19 Nov 2019 18:30
• URI: https://theses.gla.ac.uk/id/eprint/75727