Comparison of Memory, Affective Behavior, and Neuropathology in APP Knock-in Mice to 5xFAD and APP/PS1 Mice

Transgenic mouse models of Aβ amyloidosis generated by knock-in of a humanized Aβ sequence can offer some advantages over the transgenic models that overexpress amyloid precursor protein (APP). However, systematic comparison of memory, behavioral, and neuropathological phenotypes between these models has not been well documented. In this study, we compared memory and affective behavior in APP mice, an APP knock-in model, to two widely used mouse models of Alzheimer's disease, 5xFAD and APP/PS1 mice, at 10 months of age. We found that, despite similar deficits in working memory, object recognition, and social recognition memory, APP and 5xFAD mice but not APP/PS1 mice show compelling anxiety- and depressive-like behavior, and exhibited a marked impairment of social interaction. We quantified corticolimbic Aβ plaques, which were lowest in APP, intermediate in APP/PS1, and highest in 5xFAD mice. Interestingly, analysis of plaque size revealed that plaques were largest in APP/PS1 mice, intermediate in 5xFAD mice, and smallest in APP mice. Finally, we observed a significantly higher percentage of the area occupied by plaques in both 5xFAD and APP/PS1 relative to APP mice. Overall, our findings suggest that the severity of Aβ neuropathology is not directly correlated with memory and affective behavior impairments between these three transgenic mouse models. Additionally, APP may represent a valid mouse model for studying AD comorbid with anxiety and depression.