Insoluble Aβ overexpression in an App knock-in mouse model alters microstructure and gamma oscillations in the...

We studied a new amyloid-beta precursor protein (App) knock-in mouse model of Alzheimer's disease (App^NL-G-F ), containing the Swedish KM670/671NL mutation, the Iberian I716F mutation and the Artic E693G mutation, which generates elevated levels of amyloid beta (Aβ)₄₀ and Aβ₄₂ without the confounds associated with APP overexpression. This enabled us to assess changes in anxiety-related and social behaviours, and neural alterations potentially underlying such changes, driven specifically by Aβ accumulation. App^NL-G-F knock-in mice exhibited subtle deficits in tasks assessing social olfaction, but not in social motivation tasks. In anxiety-assessing tasks, App^NL-G-F knock-in mice exhibited: (1) increased thigmotaxis in the open field (OF), yet; (2) reduced closed-arm, and increased open-arm, time in the elevated plus maze (EPM). Their ostensibly anxiogenic OF profile, yet ostensibly anxiolytic EPM profile, could hint at altered cortical mechanisms affecting decision-making (e.g. 'disinhibition'), rather than simple core deficits in emotional motivation. Consistent with this possibility, alterations in microstructure, glutamatergic-dependent gamma oscillations and glutamatergic gene expression were all observed in the prefrontal cortex, but not the amygdala, of App^NL-G-F knock-in mice. Thus, insoluble Aβ overexpression drives prefrontal cortical alterations, potentially underlying changes in social and anxiety-related behavioural tasks.This article has an associated First Person interview with the first author of the paper.