Insoluble Aβ overexpression in an App knock-in mouse model alters microstructure and gamma oscillations in the prefrontal cortex, and social and anxiety-related behaviours

Abstract

We studied two new App knock-in mice models of Alzheimer's disease (App NL-F and App NL-G-F ), which generate elevated levels of Aβ 40 and Aβ 42 without the confounds associated with APP overexpression. This enabled us to assess changes in anxietyrelated 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 openarm, 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 knockin mice. Thus, insoluble Aβ overexpression drives prefrontal cortical alterations, potentially underlying changes in social and anxiety-related behavioural tasks.