Abstract

Circadian dysfunction has been described in patients with symptomatic Alzheimer’s disease (AD), as well as in presymptomatic phases of the disease. Modeling this circadian dysfunction in mouse models would provide an optimal platform for understanding mechanisms and developing therapies. While numerous studies have examined behavioral circadian function, and in some cases clock gene oscillation, in mouse models of AD, the results are variable and inconsistent across models, ages, and conditions. Ultimately, circadian changes observed in APP/PS1 models are inconsistent across studies and do not always replicate circadian phenotypes observed in human AD. Other models, including the 3xTG mouse, tau transgenic lines, and the accelerated aging SAMP8 line, show circadian phenotypes more consistent with human AD, although the literature is either inconsistent or minimal. We summarize these data and provide some recommendations to improve and standardize future studies of circadian function in AD mouse models.

Highlights

  • Numerous human studies have demonstrated that changes in circadian function are common in Alzheimer’s disease (AD) patients and contribute to disease morbidity

  • Circadian changes observed in AD patients include circadian fragmentation and decreased amplitude of circadian rhythms, which generally manifest as increased wakefulness at night and increased napping during the day (Satlin et al, 1995; Ancoli-Israel et al, 1997)

  • If these differences in baseline activity levels are altered in transgenic mouse models, it may lead to difficulty interpreting circadian behavioral analyses

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Summary

INTRODUCTION

Numerous human studies have demonstrated that changes in circadian function are common in Alzheimer’s disease (AD) patients and contribute to disease morbidity. Circadian changes observed in AD patients include circadian fragmentation and decreased amplitude of circadian rhythms, which generally manifest as increased wakefulness at night and increased napping during the day (Satlin et al, 1995; Ancoli-Israel et al, 1997). Generally hyperactive animals can be overactive during the dark phase and have a high amplitude, while hypoactive animals may be inactive during both phases and show artificially blunted amplitude If these differences in baseline activity levels are altered in transgenic mouse models, it may lead to difficulty interpreting circadian behavioral analyses. Paul et al (2018) examined the TgSwDI APP mutant mouse and observed shortened period and increased variability in activity onset/offset that were associated with blunted amplitude of neuronal firing in the SCN, providing an electrophysiological basis for rhythm disturbance. No intervals have less Bmal, Per, and Rev-erbα on average

Yes analyses
Sheehan and Musiek
Increased daily activity in Tg mice at all ages
ApoE KO to AD is unclear
Tauopathy Models
Other AD Models
Impact of AD Pathology on Clock Gene Expression
Recommendations for Circadian Studies in AD Mouse Models
CONCLUSION

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