Reduced social investigation and increased injurious behavior in transgenic 5xFAD mice

Abstract Social withdrawal and agitation/aggression are common behavioral and psychological symptoms of dementia presented by Alzheimer's disease (AD) patients, with males exhibiting more aggressive behaviors than females. Some transgenic mouse models of AD also exhibit social withdrawal and aggression, but many of these models only recapitulate the early stages of the disease. By comparison, the 5xFAD mouse model of AD exhibits rapid, progressive neurodegeneration, and is suitable for modeling cognitive and behavioral deficits at early, mid‐, and late‐stage disease progression. Anecdotal reports suggest that transgenic 5xFAD males exhibit high levels of aggression compared to wild‐type controls, but to date, indirect genetic effects in this strain have not been studied. We measured home‐cage behaviors in 5xFAD males housed in three different group‐housing conditions (transgenic‐only, wild‐type only, and mixed‐genotype) and social approach behaviors when exposed to a novel free‐roaming or restrained, wild‐type or transgenic conspecific. Transgenic‐only home cages required earlier separation due to injuries arising from aggression compared to wild‐type‐only or mixed‐genotype cages, despite no obvious increase in the frequency of aggressive behaviors. Transgenic 5xFAD males and females also spent less time investigating free‐roaming conspecifics compared to wild‐type controls, but they showed normal investigation of restrained conspecifics; the genotype of the conspecific did not affect approach behavior, and there was no aggression observed in transgenic males. These findings provide evidence in an animal model that amyloid pathology ultimately leads to avoidance of novel social stimuli, and that frequent interactions between individuals exhibiting an AD phenotype further exacerbates aggressive behaviors.