Increased aggression in males in transgenic Tg2576 mouse model of Alzheimer's disease

Abstract

Behavioural and psychological signs and symptoms of dementia encompass a wide range of neuropsychiatric disturbances which coincide with progressing cognitive decline in Alzheimer's disease (AD). Physical aggression and agitation, which occurs in 20–65% of AD patients, is physically and emotionally stressful, not only to patients but also to immediate family and caregivers. The exact mechanisms underlying the increased aggressive behaviour in AD has yet to be elucidated. We used a transgenic mouse model, denoted Tg2576, which over-expresses a mutated human amyloid precursor protein (APP) gene implicated in familial AD, to investigate aggressive behaviour of males at the stage of amyloid beta pathology preceding overt amyloid plaque deposition in the brain. The aggressive behaviour of transgenic and non-transgenic littermate males was evaluated in a standard resident–intruder test in which an isolated resident male responded aggressively toward an experimentally naïve intruder male of A/J strain. We showed that 7-month-old Tg2576 resident males demonstrated significantly higher and unchanged level of aggression towards intruder males during 3 consecutive encounters as compared to their non-transgenic littermate counterparts. These results validate further the Tg2576 mouse model of AD underscoring its usefulness in studying non-mnemonic changes in behaviour related to the disease.

Introduction

The cognitive impairment that occurs in neurodegenerative diseases such as Alzheimer's disease (AD) is often accompanied by a wide range of neuropsychiatric disturbances collectively referred to as behavioural and psychological signs and symptoms of dementia (BPSD). These BPSD, which are particularly prominent in AD, include delusions, hallucinations, activity disturbances, aggression and agitation, anxiety, depression, circadian rhythm disorders and phobias [1]. In general, BPSD encompass three major areas of behavioural disturbances: agitation and aggression, psychosis, and mood disorders [2]. Physical aggression and agitation occur in 20–65% of studied patient cohorts with dementia [3], and are most common in the moderate to severe stages of the disease [4]. Aggression and agitation are physically and emotionally stressful not only to patients but also to immediate family and caregivers [5], [6], and they often trigger placement in long-term care facilities [7]. Management of BPSD has not been yet standardized, and it depends on the type of symptoms, their severity, and frequency. The interventions employed range from behavioural and environmental approaches to, in selected cases, pharmacological treatment [8]. The exact mechanisms involved in the initiation of aggression in neurodegenerative diseases have not been identified yet. It has been proposed that an imbalance in neurotransmitters which occurs in multiple brain regions of demented patients may lead to increased aggressive behaviour [9].

Mouse models of Alzheimer's disease proved to be valuable for modeling not only cognitive impairment, but also disturbances in non-mnemonic behaviours [10], [11], [12], [13], [14], and these models are routinely used to evaluate potential therapeutic interventions targeting toxic species of amyloid beta (Aβ) protein in the context of memory impairment observed in the models [15], [16], [17], [18], [19], [20].

In our study we used a transgenic mouse model, which over-expresses a mutated human amyloid beta precursor protein (APP) gene implicated in AD, to investigate aggressive behaviour of male mice at the early stage of the increase in Aβ levels, before overt deposition of Aβ plaques in the brain. The model, denoted Tg2576, expresses human APP Swedish mutation (APP695.K670N-M671L) under the PrP hamster promoter [21]. These mice show increase in Aβ levels beginning at 6 months of age, and overt deposition of Aβ in senile plaques between 9 and 12 months [22]. Besides amyloid pathology, the model recapitulates many other neurological features of AD, including astrogliosis [23], microgliosis [24], cytokine production [25], [26], oxidative stress [27], [28], and dystrophic neurites [23]. The Tg2576 model has been one of the most widely used models to study amyloid deposition and coinciding cognitive impairment, including episodic-like memory, object recognition, and contextual conditioning [12], therefore we decided to extend the behavioural characterization of the model to aggressive behaviour. Although increased aggressive behaviour in males of other amyloid-based mouse models of AD was already reported [29], [30], [31], [32], [33], [34], [35], some of these pioneering studies included only brief, 3-min periods of evaluation of aggressive interactions as one of the test in an extensive battery of behavioural screens, while other studies reported aggression based only on a few selected variables.

In our study we used a standard method for evaluating aggression in male mice, in which an isolated resident male, kept in a larger home cage, responds aggressively toward an introduced intruder male [36]. To provide an unbiased assessment of the offensive aggressive behaviour in the Tg2576 model, we used as intruders males of A/J strain. Males of this strain do not initiate fights and do not respond to attacks by retaliating, therefore they are often used as intruders in resident–intruder tests [37], [38]. We also employed longer 10-min observation periods and administered three repeated sessions of resident–intruder encounters in order to reliably address the intensity of attacks and the possible changes in offensive behaviour due to experience with aggressive interactions [39], [40]. This testing paradigm allowed us to ascribe any observed aggressive behaviour to the experimental resident male, minimizing the potential confounding effect caused by retaliation or launching of attacks by an intruder mouse. We report that 7-month-old Tg2576 males, at the early stage of the increase in amyloid-β levels, demonstrate increased, unchanging aggressive behaviour as compared to their non-transgenic littermate counterparts.