Elsevier

Behavioural Brain Research

Volume 242, 1 April 2013, Pages 34-39
Behavioural Brain Research

Research report
Observations in THY-Tau22 mice that resemble behavioral and psychological signs and symptoms of dementia

https://doi.org/10.1016/j.bbr.2012.12.008Get rights and content

Abstract

THY-Tau22 mice constitute an animal model for tau aggregation, a hallmark in Alzheimer's disease (AD) and Tauopathies. Our previous studies have shown learning and memory deficits and changes in synaptic plasticity in the hippocampus in THY-Tau22 mice that are consistent with the learning impairments seen in AD-patients. However, behavioral disturbances are the most important problems in the management of AD and are major determinants of nursing home placement. Thus, we hypothesized that THY-Tau22 mice would demonstrate, in addition to the cognitive impairments, at least some behavioral and psychological signs and symptoms of dementia (BPSD). We found that 12 months old THY-Tau22 mice, relative to wild-type (WT) littermates display increased depression-like and aggressive behavior, co-occurring with disturbances in nocturnal activity. Moreover, these changes were linked to a decreased hippocampal concentration in serotonin, or 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin. Together these data corroborate the usefulness of the model in preclinical evaluations of therapeutic strategies that aim to reverse cognitive defects and alleviate BPSD in the human disease.

Highlights

► Mouse model. ► Dementia. ► Behavior. ► BPSD ► Serotonin.

Introduction

The clinical diagnosis of Alzheimer's disease (AD) includes deficits in memory (i.e., impaired ability to learn new information and/or to recall previously learned information), executive functioning (i.e., defects in planning, organizing, sequencing, abstracting), and language, object use and/or recognition (DSM-IV-TR, [1]). Memory loss and verbal fluency problems are the initial symptoms [2], but patients with AD are also susceptible to apraxia [3] and agnosia [4]. Changes in personality, deterioration of social skills, emotional blunting, diurnal rhythm disturbances and behavioral disinhibition, occur in AD patients as well [5]. Apathy, accompanied by social withdrawal and depression [6], and agitation, which may lead to aggression [7] are commonly referred to as behavioral and psychological signs and symptoms of dementia (BPSD; [8]). Notably, such BPSD are distressing to families and caregivers, and, e.g., aggressive behavior ranks amongst the most common cause for institutionalization [9]. Physical aggression occurs in 20–65% of patients with dementia [10], [11], whereas depression and altered sleep-wake patterns are very common in pre-symtomatic AD, and often are the first disease manifestations before any cognitive changes appear [12], [13].

Over the past decade, transgenic mutant mouse models have been crucial for much of the progress in research on AD pathogenesis and possible treatment [14], [15], [16], [17], [18]. Many of these models not only mimic AD neuropathology, but also behavioral and cognitive symptoms observed in clinical AD. Lalonde et al. [19] recently reviewed the occurrence of BPSD-like behavioral changes in APP transgenic mice, most of which obviously mimic AD neuropathology only partially. However, it is becoming increasingly apparent that tau pathology also plays an equally important and synergistic role in AD etiology [20]. Therefore, it is critically important to investigate if BPSD-like changes do not only relate to APP- and/or amyloid-related histopathology [55], but also to neurofibrillary tangle (NFT)- and tau pathology.

In this paper, we therefore investigated the possible occurrence of BPSD-like behavioral changes in THY-Tau22 mice that express human 4-repeat tau and display phosphorylated tau aggregation in hippocampus, amygdala and other limbic brain structures as well as cognitive changes. In the THY-Tau22 transgenic mouse model the NFT-like formation starts from 6 months in the CA1 region. Older mice at 12 months show full blown NFT, aggregates made out of hyperphosphorylated tau protein, in the hippocampus, and no NFT could be observed in the cortex, up to 16 months of age [21], [22], [23], [24].

Evidence from animal and human studies suggest that an alteration in serotonin, or 5-hydroxytryptamine (5-HT) may underlie the changes observed and reported in mood, aggression, feeding, and sleep. Several post mortem, platelet binding studies in humans, have shown negative associations between levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, and depressive symptoms [25], [26], [27], [58]. Increased aggression in AD patients may be due to degeneration of 5-HT neurons [28], [29], [61]. Low concentrations of 5-HIAA in cerebrospinal fluid have been associated with severe aggression in primates as well [30], [31]. Moreover, a recent study by Mosienko et al. [57] shows that mice deficient in brain serotonin exhibited increased depression-like behavior accompanied by strong aggressiveness.

The purpose of our study is to investigate BPSD in the THY-Tau22 mouse model and examine changes in the levels of serotonin in these mice to address unresolved questions that may be the clinical and therapeutic importance.

Section snippets

Animals

Ten THY-Tau22 heterozygous male mice aged 12 months and a corresponding number of wild-type (WT) controls were generated as previously described [21], [22], [23]. All animals were kept in standard animal cages (5 per cage) under conventional laboratory conditions (12 h/12 h light–dark cycle, 22 °C), with ad libitum access to food and water (unless stated otherwise). To examine changes in activity, altered agitation and aggression levels, and depression-related behavior in tau mutant mice, we

Increased agitation and aggressive behaviors in THY-Tau22 mice

Recordings for each 30-min interval revealed altered cage activity profiles in tau mutant mice with increased agitation during the initial exploration/introduction phase and hyperactivity during the dark phase of the cycle (RM-ANOVA F(1,44) = 6.32; P < 0.05; Fig. 1A). The tube test of aggression and dominance revealed that tau mutant mice repeatedly pushed the opponent mouse out of the tube, thus resulting in more wins (t(18) = 2.44; P < 0.05; Fig. 1B).

Increased depression-like behaviors in THY-Tau22 mice

During the 6-min period of the tail suspension

Discussion

Many genetically altered mice have been designed to help understand the role of specific gene mutations in the pathogenesis of AD) based on the realization that specific mutations in the genes for amyloid precursor protein (APP) and tau are associated with early-onset familial AD. Most etiological and treatment studies on mouse models of AD however focused on neurocognitive outcome measures, whereas Lalonde et al. [19] recently emphasized that behavioral changes reminiscent of BPSD occur in APP

Acknowledgments

Research supported by FWO-Vlaanderen (grant G.0327.08 to DB and RD; FWO junior scholarship to AVdJ). The authors wish to thank Zsuzsanna Callaerts-Vegh for excellent technical advice, and Tine Stuyven and Daphne Talboom for help with the experiments. This work has been developed and supported through the LABEX (excellence laboratory, program invest for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) and by grants from the French

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