Elsevier

Behavioural Brain Research

Volume 359, 1 February 2019, Pages 408-417
Behavioural Brain Research

Research report
Cognitive decline in Tg2576 mice shows sex-specific differences and correlates with cerebral amyloid-beta

https://doi.org/10.1016/j.bbr.2018.11.022Get rights and content

Highlights

  • Tg2576 mice develop cognitive impairment beginning at the age of 8 months.

  • Female Tg2576 mice show worse reference memory than males at 12–16 months.

  • Cognitive impairment is sex-dependently correlated to Aβ (soluble and deposits).

Abstract

Patients suffering from Alzheimer’s disease show a sex-dependent decline of cognitive function. The aim of this investigation was to show these differences in an animal model for Alzheimer’s disease and to determine whether this effect is correlated to amyloid-beta-induced pathophysiological changes. Therefore, we assessed cognitive performance with the modified hole-board test in female and male Tg2576 and wild type mice at the age of 6, 8, 10, 12, 14, and 16 months and correlated these findings to the total amount of soluble amyloid-beta and insoluble amyloid deposits in the brain. Tg2576 mice perform worse than wild types. Female Tg2576 mice develop an accentuated cognitive impairment (wrong choice total) beginning at the age of 12 months compared to their male littermates. Alterations in the mice’s behaviour do not show interference with these deficits. Cognitive impairment is correlated to the amount of soluble amyloid-beta and insoluble amyloid deposits in the brain in a sex-dependent manner.

Introduction

Epidemiological studies demonstrate that female patients are more likely to suffer from Alzheimer disease (AD) than male patients [1,2]. Further, women with AD show a more rapid and pronounced decline in their mental state than men, while the final mental state is comparable [3]. To elucidate the underlying mechanisms animal models are needed, which reflect the human situation. To date, just a few studies investigated the effect of female gender on cognitive function in AD models but none of these studies focused on the time course of neurobehavioural impairment [[4], [5], [6]].

The big advantage of preclinical AD models lies in the possibility to concomitantly analyse cognitive function and histopathological findings. Next to tauopathy, synaptic failure and mitochondrial dysfunction, an increased amount of amyloid-beta (Aβ) in the brain is discussed as the key pathophysiological finding [7,8]. With respect to gender, studies have shown that with increasing age the concentration of Aβ in female mice outreaches that of their male littermates [9,10]. However, these studies did not investigate neurobehavioural parameters. The Tg2576 mouse model represents an ideal tool to investigate this amyloidopathy [11,12].

Therefore, the primary aim of the current study was to describe the phenotype of the Tg2576 model with focus on sex-specific cognitive and behavioural impairment over time. To achieve this, we characterised the time course of impairment by using the modified hole-board test in mice aged 6, 8, 10, 12, 14, or 16 months in female and male mice. Further we investigated the correlation between the amount of Aβ in the brain and the findings of the modified hole-board test. In order to detect potential targets for future research in the context of sex dependent deterioration of cognitive or behavioural function we analysed molecular mechanisms such as inflammation, apoptosis, or changes in the glutaminergic system as secondary endpoints.

Section snippets

Methods

The following experimental procedures on animals were approved by the Governmental Animal Care Committee (Regierung von Oberbayern, Maximilianstr. 39, 80538 Munich, Germany, Dr. B. Wirrer, Deputy Veterinary Director, registration numbers 55.2-1-54-2531-1-10, date of approval: 2010/03/03, and 55.2-1-54-2532-149-11, date of approval: 2012/01/24).

Cognitive and behavioural testing – differences between Tg2576 and wild type mice

Reference memory function (total number of wrong choices) and working memory function (repeated choices) were impaired in Tg2576 mice when compared to wild type mice. This impairment developed at the age of 8 months and persisted up to the age of 16 months. (Fig. 1A and B) There was no difference in the overall cognitive performance (time complete). (Fig. 1C, Table 1)

The mice’s anxiety assessed by time on board, but not regarding latency first board entry was decreased in Tg2576 mice beginning

Discussion

The aim of this investigation was to determine the sex-specific time course of cognitive and behavioural impairment in Tg2576 mice. In contrast to wild type mice, Tg2576 animals showed a decline in explicit and working memory, beginning at the age of 8 months, which was accompanied by decreased anxiety, starting at the age of 10 months. Female Tg2576 mice showed an accentuated deficit in reference memory compared to their male littermates, beginning at the age of 12 months. Female Tg2576 mice

Conclusions

In conclusion, Tg2576 mice develop a more profound cognitive impairment beginning at the age of 8 months compared to their wild type littermates. At the ages of 12–16 months female animals show worse reference memory than male animals, which is not overlaid by alterations in the mice’s behaviour. There is a sex-dependent correlation of this dysfunction to the amount of soluble Aβ and amyloid deposits, suggesting that females have a higher sensitivity to the toxic effects of amyloid load than

Conflicts of interest

The authors declare that there are no conflicts of interest.

Source of funding

This study was funded by institutional support. There was no involvement of any sponsor in study design, collection, analysis and interpretation of data, writing of the report, and in the decision to submit the article for publication.

Authors’ contribution statements

SS: designed and performed experiments, conducted analysis, wrote manuscript; MB: designed experiments, conducted analysis, provided critical feedback on manuscript; GR: designed experiments, provided critical feedback on manuscript; KK: designed and performed experiments, provided critical feedback on manuscript; SB: performed experiments, provided critical feedback on manuscript; DF: performed experiments, provided critical feedback on manuscript; KZ: performed experiments, provided critical

Acknowledgements

We are indebted to Andreas Blaschke, Maximilian Musiol, Nina Bayer, and Claudia Kopp for performing parts of the analysis procedure.

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