Mouse Models of Alzheimer's Disease: New Behavioral Approaches

Recent advances in gene editing has allowed the generation of advanced rodent research models, mimicking some aspects of human conditions. For neurodegenerative disorders such as Alzheimer’s Disease, a long list of models exist with variable pathologies and not always convincingly linking pathology with behavioural phenotypes. As the field is moving more towards the use of in vitro models, it is nevertheless recognised that validation of cellular research and drug discovery must ultimately include systems endpoints, so that e.g. benefits and detrimental impacts of treatments in terms of health, behaviour and most importantly cognition are observed.

In order to develop a paradigm that allows accelerated insights into multiple behavioural aspects, we have designed and validated a novel behavioural paradigm, OF-NO-SI, which comprises activity measures in a circular open field (OF) arena, followed by a novel object (NO) stage and lastly presentation of a sex and age-matched conspecific for social interaction (SI) in one session. Each segment consisted of two repeated trials to measure within- and between-trial recognition memory. Data were correlated with post-mortem molecular outcomes.

This presentation will discuss results from different mouse lines (rTg4510 tau over expression model, 5X APP overexpression model, and in house generated PLB lines expressing low levels of tau and/or APP). During OF-NO-SI, transgenic mice displayed deficits in object and conspecific exploration and recognition memory. The paradigm robustly detected differences between models, genotypes and sexes for activity and cognitive measures.

Both overexpression models, 5X and rTg4510, displayed hyperactivity and spent less time interacting with object/stranger compared to WTs. Compared to low expression models (PLBAPP/PLBTau), the overexpression models differed only in their sustained hyperactivity. Despite being on the same genetic background, ‘control’ animals from different lines did not behave the same. Strongest correlations between behavioural and molecular phenotypes were detected for inflammatory markers.

Overall, disease-relevant behavioural phenotypes were identified, but our results identified over-expression per se as a potential confounder, and emphasise essential issues with control littermates.

Learning Objectives: 

1. Discuss and compare genetically modified mouse models of dementia.

2. Explain a new stream-lined behavioural tests paradigm.

3. Describe behavioural and cognitive phenotypes detected in the paradigm.