Generation of a hybridAppNL-G-F/NL-G-F×Thy1-GCaMP6s+/-Alzheimer disease mouse mitigates the behavioral and hippocampal encoding deficits ofAPPknock-in mutations ofAppNL-G-F/NL-G-Fmice

ABSTRACTIn 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 (Aβ) pathology and cognitive impairment without physiologically unrealisticAppoverexpression. This study investigated the effect of familial AD-linkedAppmutations on hippocampal CA1 neuronal activity and function. To enable calcium imaging of neuronal activity,AppNL-G-F/NL-G-Fknock-in (APPki) mice were crossed withThy1-GCaMP6s+/-(C-TG) mice to generateAppNL-G-F/NL-G-F×Thy1-GCaMP6s+/-(A-TG) mice, which were characterized at 12 months of age. A-TG mice exhibited Aβ 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 Aβ 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 ofAPPmutations may have been mitigated through genetic mechanisms when APPKi mice were crossed with C-TG mice.