The influence of APOE isoform on everyday memory and the hippocampal c-Fos response

Stuart, Alexander Cameron (2022) The influence of APOE isoform on everyday memory and the hippocampal c-Fos response. Doctoral thesis (PhD), University of Sussex.

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Abstract

Apolipoprotein E (APOE) is a key mediator of lipid homeostasis within the periphery and CNS. Of the primary allelic isoform variants of APOE (APOE2, APOE3, APOE4), APOE4 increases the risk of late-onset Alzheimer’s disease (LOAD).

APOE4 is associated with long-term episodic memory dysfunction in mouse models, but there is little investigation of rapid acquisition of ‘everyday memory’, formed over short timescales (minutes to hours). Further, while evidence suggests that APOE4 disrupts neuronal function via multiple mechanisms, the effect of APOE on the activity of ‘neuronal ensembles’, sparse groups of activated neurons crucial for behaviour, has yet to be investigated.

This thesis aimed to assess the influence of APOE isoform, age, and sex on trajectories of everyday memory, while in parallel, the influence of these same factors on hippocampal neuronal ensemble activation following behaviour. These questions were addressed using APOE targeted replacement mice, first with longitudinal assessment using an everyday memory maze task, and second via immediate-early gene (IEG) measurements following environmental novelty.

Our results highlighted age, sex, and APOE isoform-dependent interactions in everyday memory, namely with E4-TR mice exhibiting impairments in early-age learning, mid-aged memory accuracy, and late-age learning in female mice. We suggest mild APOE-dependent differences in everyday memory may be superseded by longer-term episodic memory impairments.

In parallel, we observed an enhanced hippocampal CA1 ensemble size in E4-TR mice from young-to-mid age. Further, this was accompanied by genotype-sex interactions in hippocampal IEG network correlations, putative GABAergic innervation, IEG and APOE mRNA expression. Finally, the APOE4 CA1 ensemble size increase was not associated with changes in dendritic spine density or spine ‘synaptic occupation’.

We suggest these results reflect early and diverse phenotypic effects of APOE4 on hippocampal function. Further investigation of the underlying cell and circuit-level mechanisms which induce mild cognitive effects decades prior to extensive pathology is needed.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0438 Psychiatry, including Psychopathology > RC0513 Psychoses > RC0521 Dementia > RC0522 Presenile dementia > RC0523 Alzheimer's disease
Depositing User: Library Cataloguing
Date Deposited: 07 Jun 2022 13:35
Last Modified: 07 Jun 2022 13:35
URI: http://sro.sussex.ac.uk/id/eprint/106230

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