Impaired Cognitive Flexibility With Preserved Learning in an Amyloid Precursor Protein Knock-In Mouse Model of Amyloidopathy.

Alzheimer's disease is a debilitating neurodegenerative condition characterized by amyloid beta plaques and tau neurofibrillary tangles, which leads to progressive cognitive decline. Several new mouse models of fast amyloid deposition have been generated with compound mutations, but how these affect high-level cognitive function is still not fully understood. Four cohorts of a second-generation amyloid precursor protein knock-in mouse model, AppNL-G-F/NL-G-F, which develops aggressive amyloidopathy, were compared with two different control groups that do not produce plaques (AppNL/NL and wildtype littermates), on touchscreen-based tests of learning and cognitive flexibility. AppNL-G-F/NL-G-F mice learned to discriminate between two visual stimuli during the pairwise visual discrimination (PVD) task but were impaired when the reward contingencies were reversed (the PVR task). Analyses of the correction trials indicated perseverative behavior. One cohort was further tested on the touchscreen Extinction test, which isolates the ability to withhold responding to a previously rewarded stimulus. The AppNL-G-F/NL-G-F mice extinguished their responding no differently than the AppNL/NL control group. These results indicate that compound mutations in App driving fast accumulation of plaques in this mouse model impair cognitive flexibility and may serve as a preclinical target for putative therapeutic drugs.