The AppNLGF mouse model of amyloid pathology: age‐related behavioural characterisation

Abstract

AbstractBackground2nd generation knock‐in models of amyloid pathology have been generated to overcome the non‐specific effects of the overexpression of human APP mutation in mice (Saito et al., 2014). AppNLGF mice are a relatively new model that expresses human mutant APP at endogenous levels without cellular artefacts noted in transgenic mice (Sasaguri et al., 2022). The key question of how this more restricted expression of human APP mutations influences behaviour in mice has yet to be fully understood. The aim of this study was to establish the profile of memory and anxiety processes in AppNLGF mice with age.MethodsTo monitor the effect of progressive Aβ deposition, AppNLGF mice underwent testing at 4‐6, 8‐10, 12‐14, and 22‐23 months old. Behavioural tests were selected to interrogate key neuronal networks affected in AD. Spatial recognition memory was assessed using the Object Location Test (OLT). Spatial working memory was tested using Spontaneous Alternation (SA) testing. Anxiety‐like behaviours were observed with Open Field (OF) and Elevated Plus Maze (EPM) tests.ResultsDuring OLT, AppNLGF mice showed no significant difference in object discrimination compared to control animals at all ages tested. However, at 8‐10 and 22‐23m/o, AppNLGFs were unable to discriminate the object in the novel location. Furthermore, AppNLGFs showed intact alternation in SA testing until 22‐23m/o. Interestingly, AppNLGFs exhibited decreased inner zone exploration in OF testing at 22‐23m/o, but consistently showed substantial preference for open arms in the EPM test from as early as 4m/o.ConclusionThe AppNLGF model shows subtle cognitive deficits that are most apparent at an advanced age. The severity of the deficits is relatively mild compared to transgenic models assessed on similar tasks. This is probably related to the absence of overexpression‐related artefacts and may speak to the more subtle effects of amyloid on synaptic plasticity. These mice also lack key cellular AD hallmarks such as tau hyperphosphorylation and cell loss. Nevertheless, AppNLGFs robustly display substantial early anxiolytic‐like behaviour in the EPM test, and anxiogenic‐like behaviour in the OF test at an advanced age, suggesting that amyloid pathology may contribute to behavioural and neuropsychiatric changes.