Select Page


1Behavioral Pharmacology, PsychoGenics, Inc., Paramus, NJ, USA;
2TissueVision, Somerville, MA, USA;

Background: Behavioral aggression is a common neuropsychiatric symptom that coincides with progressive cognitive decline in adults with Alzheimer’s disease (AD). One of the key hallmarks of AD is progressive accumulation of amyloid-beta (Aβ) throughout the brain. The present study was aimed at measuring non-cognitive behaviors such as aggression and relevant pathologies such as plaque load and distribution in mutant mice expressing human APP, namely the APP/PS1 (APPsw/PS1 (m146L)) and TASD41 (hAPP751 with the London V717I9/Swedish double mutation K670M/N671L).

Methods: In the current study, we were interested in examining progression of behavioral manifestations in male mice of both the APP/PS1 and TASD41 lines. The resident-intruder paradigm was used to assess aggression in AD mice. We also utilized proprietary algorithm-based behavioral platform, the SmartCube® System, to assess whole animal behavior longitudinally. To compliment these behavioral outputs, we additionally performed Serial Two-Photon whole brain imaging and analysis of the distribution, size and density of Aβ-plaques in young and aged AD mice using the TissueCyte® imaging platform.

Results: The present findings demonstrate increased aggressive behavior in aged APP/PS1 and TASD41 male mice compared to wild-type littermates. We also demonstrate pharmacological attenuation of aggression in AD mice with acute administration of either antipsychotic (Risperidone) or anxiolytic (Busipirone). Using sophisticated algorithm-based system, SmartCube®, we were able to identify a phenotype effect and distinct behavioral changes in male AD mice as early as 5 months of age that progressed over time. In line with the behavioral data, our whole brain TissueCyte® based analyses suggests that younger mice (∼4-5 months) exhibit very sparse parenchymal plaques while aged mice (>7 months) show a clear progression in the number/size of plaques and display differential increases in regional plaque load number/size.

Conclusions: In summary, we demonstrate clear aggressive behavior and pharmacological validation in aged, male mouse models of amyloidosis, with more advanced computer vision systems identifying distinctive behavioral patterns and discriminating the phenotype at early disease stages. Together with the region-specific progression of plaque densities, these models present a valuable tool for early intervention and improved assessment of potential therapeutic approaches for AD and in particular AD-induced aggression.