Longitudinal Assessment of Working Memory Performance in the APPswe/PSEN1dE9 Mouse Model of Alzheimer's Disease Using an Automated Figure-8-Maze.

Fran C Van Heusden,August B Smit,Sara Palacín I Bonsón,Oliver Stiedl,Ronald E Van Kesteren

doi:10.3389/fnbeh.2021.655449

Fran C Van Heusden, August B Smit + Show 3 more

Open Access

https://doi.org/10.3389/fnbeh.2021.655449

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with a long preclinical and prodromal phase. To enable the study of disease mechanisms, AD has been modeled in many transgenic animal lines and cognitive functioning has been tested using several widely used behavioral tasks. These tasks, however, are not always suited for repeated longitudinal testing and are often associated with acute stress such as animal transfer, handling, novelty, or stress related to the task itself. This makes it challenging to relate cognitive dysfunction in animal models to cognitive decline observed in AD patients. Here, we designed an automated figure-8-maze (F8M) to test mice in a delayed alternation task (DAT) in a longitudinal manner. Mice were rewarded when they entered alternate sides of the maze on subsequent trials. Automation as well as connection of the F8M set-up with a home cage reduces experimenter interference and minimizes acute stress, thus making it suitable for longitudinal testing and facilitating clinical translation. In the present study, we monitored cognitive functioning of 2-month-old APPswe/PSEN1dE9 (APP/PS1) mice over a period of 4 months. The percentage of correct responses in the DAT did not differ between wild-type and transgenic mice from 2 to 6 months of age. However, 6-month-old mice displayed an increase in the number of consecutive incorrect responses. These results demonstrate the feasibility of longitudinal testing using an automated F8M and suggest that APP/PS1 mice are not impaired at delayed spatial alternation until 6 months of age under the current experimental conditions.

Highlights

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders and the most common cause of dementia (Blennow et al, 2006)
Test phase 4 did not show any significant differences. These results indicate that amyloid precursor protein (APP)/PS1 mice had reduced Choice reaction time (CRT) during the training phase and test phase 3
We designed an automated F8M to monitor cognitive function in AD mice in a longitudinal manner. Using this set-up, we tested APP/PS1 mice from 2 to 6 moa to determine the feasibility of longitudinal testing and the sensitivity of the

Summary

Introduction

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders and the most common cause of dementia (Blennow et al, 2006). The disease is characterized by extracellular amyloid beta plaques and intracellular tau tangles (Braak and Braak, 1990). These neuropathological hallmarks are especially pronounced in the hippocampal formation. Hippocampal atrophy has been detected at an early disease stage and correlates with changes in the cognitive status of patients, progressing from normal functioning to mild cognitive impairment (MCI) and AD (Ikeda et al, 1994; Jack et al, 2000; Mueller et al, 2010; Andrews et al, 2013). It is crucial to perform animal studies in which disease-relevant cognitive functioning is monitored over extended periods of time

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