Generation of a hybrid AppNL-G-F/NL-G-F xThy1-GCaMP6s+/- Alzheimer disease mouse mitigates the behavioral and hippocampal encoding deficits of APP knock-in mutations of AppNL-G-F/NL-G-F mice

In contrast to most transgenic mouse models of Alzheimer disease (AD), knock-in mice expressing familial AD-linked mutations of the amyloid precursor protein (App) gene exhibit stereotypical age-dependent amyloid beta (A{beta}) pathology and cognitive impairment without physiologically unrealistic App overexpression. This study investigated the effect of familial AD-linked App mutations on hippocampal CA1 neuronal activity and function. To enable calcium imaging of neuronal activity, AppNL-G-F/NL-G-F knock-in (APPki) mice were crossed with Thy1-GCaMP6s+/- (C-TG) mice to generate AppNL-G-F/NL-G-FxThy1-GCaMP6s+/- (A-TG) mice, which were characterized at 12 months of age. A-TG mice exhibited A{beta} pathology in the hippocampus. In several configurations of an air-induced running task, A-TG mice and C-TG mice were equally successful in learning to run or to stay immobile. In the Morris water place test, A-TG mice were impaired, but learned the task. Comparisons of hippocampal CA1 neuronal activity in the air-induced running task showed that A-TG mice displayed neuronal hypoactivity both during movement and immobility. A-TG mice and C-TG CA1 neuronal encoding of distance or time in the air induced running task were not different. These results suggest that knock-in of familial AD-linked mutations in A-TG mice results in A{beta} pathology, neuronal hypoactivity, and cognitive impairment without severely affecting CA1 neuronal encoding. In comparison to APPki mice, A-TG mice had less severe AD-like memory impairments at 12 months of age (Saito et al., 2014; Mehla et al., 2019), suggesting that the disease onset was delayed in A-TG mice. The effect of APP mutations may have been mitigated through genetic mechanisms when APPKi mice were crossed with C-TG mice.