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

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 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 memory, 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. Highlights App NL-G-F KI mice displayed differing anxiety behaviours in two tests of anxiety. Prefrontal gamma was no longer NMDA-receptor dependent in App NL-G-F KI mice. Prefrontal expression of Grin2b was reduced in App NL-G-F KI mice. DTI found structural alterations in the hippocampus and prefrontal cortex in App NL-G-F KI mice.