The AppNLGF mouse model of amyloid pathology: Characterisation of cognitive function and neuronal activity

Boxall, Ffion 2025. The AppNLGF mouse model of amyloid pathology: Characterisation of cognitive function and neuronal activity. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Transgenic mouse models overexpressing Amyloid Precursor Protein (APP) have been widely used to model the amyloid-beta (Aβ) pathology of Alzheimer’s Disease (AD), but the overexpression of other APP fragments may result in artificial phenotypes (Sasaguri et al., 2022). The AppNLGF mouse, a newer knock-in model that expresses humanised mutant APP at endogenous levels, avoids such artefacts (Saito et al., 2014). However, relatively little is known about how this more restricted expression of mutant APP influences cognition and neural activity. This thesis therefore aimed to characterise memory function (including episodic-like and spatial working memory), and anxiety-like behaviour in AppNLGF mice across a range of ages, while also examining neural activity using in vivo two-photon Calcium (Ca2+) imaging and immediate early gene (c-fos) expression. Behavioural deficits in AppNLGF mice were mild and predominantly emerged in the oldest age group (22-23 months). At this age, AppNLGF mice exhibited intact object novelty memory but were impaired in the object location and object-in-place spatial memory tasks. AppNLGFs also exhibited impaired performance in the spontaneous alternation spatial working memory task at 22-23 months. Moreover, AppNLGFs exhibited increased thigmotaxis in the open field at 22-23 months, consistent with anxiety-like behaviour. In contrast, consistent disinhibitory or anxiolytic-like behaviour in the elevated plus maze was observed from as early as 4 months of age. Subtle changes in neuronal activity were also observed: at 22-23 months, AppNLGFs exhibited reduced stimulus-evoked Ca2+ transients in the retrosplenial cortex (RSC), a region involved in navigation and episodic memory that exhibits early Aβ pathology (Alexander et al., 2023; Buckner et al., 2005; Klunk et al., 2004). While c-fos expression in the RSC remained preserved at 14-16 months, reduced basal levels were observed in the hippocampus, a region critical for spatial and episodic memory that also exhibits early Aβ pathology (Rao et al., 2022). Together, these findings suggest that AppNLGF mice exhibit mostly mild, age-dependent cognitive impairments and reduced neuronal activity. The modest phenotype likely reflects the absence of overexpression-related artefacts and may suggest a subtle effect of amyloid on synaptic dysfunction. Whilst these findings support the relevance of AppNLGFs to early or preclinical AD, the subtlety of its phenotype may limit its utility for evaluating the efficacy of therapeutic interventions.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Psychology
Date of First Compliant Deposit:	25 September 2025
Last Modified:	25 Sep 2025 15:18
URI:	https://orca.cardiff.ac.uk/id/eprint/181345

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