Age-related changes in social behaviours in the 5xFAD mouse model of Alzheimer’s disease

Abstract

In addition to memory impairments, patients with Alzheimer's disease (AD) exhibit a number of behavioural and psychological symptoms that can affect social interactions over the course of the disease. While altered social interactions have been demonstrated in a number of mouse models of AD, many models only recapitulate the initial stages of the disease, and these behavioural changes have yet to be examined over the course of disease progression. By performing a longitudinal study using the 5xFAD mouse model, we have demonstrated that transgenic females exhibit progressive alterations in social investigation compared to wild-type controls. Transgenic females exhibited an age-related reduction in interest for social odours, as well as reduced investigative behaviours towards novel conspecifics in a novel environment. However, transgenic mice exhibited no obvious olfactory deficits, nor any changes in scent-marking behaviour compared to wild-type controls, indicating that changes in investigative behaviour were due to motivation to engage with a social stimulus. This evidence suggests that transgenic 5xFAD females exhibit increased social anxiety in novel environments compared to wildtype controls. Overall, transgenic 5xFAD female mice mimic some features of social withdrawal observed in human AD patients suggesting this strain may be suitable for modelling aspects of the social dysfunction observed in human patients.Keywords social behaviors; transgenic mice; 5xFAD, Alzheimer's disease Evidence for increased sociability in the 3xTg-AD mouse model has also been presented [19], but the Tg2576 strain exhibits no effect of AD pathology on sociability [17]. Overall, these results indicate that some mouse models of AD exhibit changes in social behaviour that include altered aggression and sociability. However, many transgenic mouse models of AD (e.g., 3xTg-AD, APP/PS1, and Tg2576) exhibit a slow rate of amyloid beta (Ab) accumulation and can only model the initial phase of the disease, which does not include widespread neurodegeneration [20].By comparison, the 5xFAD strain exhibits rapid development and progression of amyloid plaques and neurodegeneration, allowing effects to be tracked across early-, mid-, and late-stage disease progression [20,21]. There is increasing evidence that 5xFAD mice exhibit a range of social deficits that, in some cases, mirror the social symptoms presented by AD patients. Transgenic 5xFAD 9-month-old male mice and 12-month-old male and female mice demonstrate deficits in nest building, a behaviour that has been associated with affiliative behaviours [22,23]; however, they also engage in more homecage social behaviours than wild-type controls [24]. Transgenic 5xFAD mice also exhibit impaired social recognition memory at 9-months of age [24], consistent with memory deficits exhibited in this strain and human AD patients.While these results suggest that the 5xFAD strain exhibit social deficits, a comprehensive investigation of social behaviours in this strain has not yet been performed. The p...

MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease

“…While mice are generally social animals [ 65 ], in the current studies the E4FAD mice did not display a preference for a mouse compared to the empty cage, indicative of reduced sociability, as measured using the three-chamber test. Similarly, though the 5xFAD mice did spend significantly more time with the mouse than the empty cage, it did so to a lesser degree than the WT mice, consistent with previous studies demonstrating reduced sociability in this mouse AD model, which progresses from 3 months of age onward [ 66 ]. The reduced social interaction by the 5xFAD mice was not apparent in the 5xFAD/MMP9KO mice, suggesting that removal of the MMP9 gene in this mouse AD model beneficially impacted sociability.…”

“…Likewise, recognition memory has been shown to emerge at 4 months of age [ 103 ] in one study and at 9 months of age in another [ 67 ]. These findings indicate behavioral observations can vary considerably from one experiment to another and memory impairment can be specific to context, modality, and/or environment [ 66 ]. Because the E4FAD and the 5xFAD made few errors by day 5, it is difficult to discern whether the SB-3CT treatment or the MMP9 gene knockout had any impact on spatial memory in these studies.…”

Anxiety, Impaired Social and Aggressive Behaviour Correlates With Cognitive Decline Accompanied by Molecular Alterations in Older SAMP8 Males

“…Social dysfunction observed in human AD patients has been observed in transgenic AD mice as well [32,36]. In our study, 12-month-old male SAMP8 mice exhibited social behaviour deficits by presenting no differences in the chambers preference and consequently interacting for less time with the intruder.…”

Alzheimer’s Disease and Empathic Abilities: The Proposed Role of the Cingulate Cortex

“…These results have been to some extent confirmed in mouse models that express the human genes containing FAD mutations; thus, it has been proven that 150 these mouse models with cognitive dysfunctions also 151 develop early social disturbances [9, 35,36].…”