Behavioural and neuropathological features of the AppNL-F and AppNL-G-F mouse models of Alzheimer's disease

Anxiety and social withdrawal often emerge during Alzheimer’s disease (AD); investigating their neurobiological underpinnings is thus important. To this end, we examined social and anxiety-related behaviours in male and female AppNL-F and AppNL-G-F mice aged 8 and 15-months, and characterized the microstructural integrity of neural tissue using ex vivo diffusion tensor imaging. These novel APP knock-in mice have translational advantages given that they model Aβ pathology without the overexpression of APP. The AppNL-G-F mice exhibit a threefold-faster Aβ deposition compared to the AppNL-F mice: this provides the added opportunity to explore the differential effects of soluble Aβ oligomers and insoluble fibrillar Aβ on behaviour and its neural substrates. Using the Crawley 3-chamber protocol, preference for sociability in the 8 and 15-month old AppNL-F and AppNL-G-F mice was intact. A mild impairment in preference for social novelty in the 8-month old AppNL-F and AppNL-G-F mice, as well as a mild social olfaction deficit in the 8-month old female AppNL-G-F mice and the 15-month old AppNL-F and AppNL-G-F mice, was observed. Regarding the anxiety assessing tasks, both the 8 and 15-month old AppNL-F mice displayed unaltered behaviour in the open field and elevated plus-maze; in contrast, the 8-month old AppNL-G-F mice combined an ostensibly anxiogenic open field profile with an ostensibly anxiolytic plus-maze profile. This ostensibly anxiolytic plus-maze profile persisted in the 15-month old AppNL-G-F mice. Together, these results suggest that the AppNL-G-F mouse may enable modeling of the neurobiological links between emergent disinhibition-type behaviour and AD. Consistent with this suggestion, notable microstructural alterations were observed in the orbitofrontal and anterior cingulate cortices of both the younger and older AppNL-G-F mice. Microstructural alterations did not emerge in the AppNL-F mice until the later age point. Insoluble Aβ likely contributes to the behavioural and neuropathological characteristics seen in the AppNL-G-F, but not the AppNL-F, mice.