Elsevier

Neurobiology of Aging

Volume 35, Issue 8, August 2014, Pages 1813-1820
Neurobiology of Aging

Regular article
Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer's disease with plaques and tangles

https://doi.org/10.1016/j.neurobiolaging.2014.02.011Get rights and content

Abstract

Several studies have highlighted the frequency of sleep disturbances in Alzheimer's disease (AD). However, whether they are secondary to the disease or per se increase its risk remains to be fully investigated. The aim of the current investigation was to study the effect of sleep deprivation (SD) on the development of AD phenotype in a transgenic mouse model with plaques and tangles, the 3xTg mice. We evaluated the functional and biological consequences on 3xTg mice that underwent 4 hours sleep restrain per day for 8 weeks. Compared with controls, behavioral assessment showed that SD-treated mice had a significant decline in their learning and memory. Although no differences were detected in the levels of soluble amyloid-β peptides, the same animals displayed a decrease in tau phosphorylation, which associated with a significant increase in its insoluble fraction. In addition, we observed that SD resulted in lower levels of postsynaptic density protein 95 and increased glial fibrillary acidic protein levels. Finally, although total levels of the transcription factor cellular response element binding protein were unchanged, its phosphorylated form was significantly diminished in brains of sleep-deprived mice when compared with controls. Our study underlines the importance of SD as a chronic stressor, which by modulating biochemical processes influences the development of memory impairments and AD neuropathologies. Correction of SD could be a viable therapeutic strategy to prevent the onset or slow the progression of AD in individuals bearing this risk factor.

Introduction

Alzheimer's disease (AD) is the principal cause of dementia in the elderly individuals. With increasing human longevity and the absence of a cure, AD has become both a major public health challenge as well as a heavy economic burden worldwide. In its sporadic form, which represents most of the total cases, the disease is generally considered as the result of the interaction between genetic and environmental risk factors. As an environmental risk factor linked to AD, chronic stress has been suggested to play a relevant role in the age of onset and development of the neuropathology (Wilson et al., 2006). Among other things, chronic stress can result in significant sleep cycle disturbances, which have a wide range of effects on different organs including the central nervous system.

Recently, many studies support a relationship between sleep deprivation (SD) and neurodegenerative diseases. In longitudinal studies, subjects with sleep disturbance were more likely to develop and/or have a diagnosis of AD or cognitive decline at follow-up (Cricco et al., 2001, Osorio et al., 2011, Tranah et al., 2011). Transgenic mouse model of AD manifest abnormalities of sleep behavior, implying that the development of the disease underlines these sleep disorders. Yet, manipulation of sleep cycle in the same murine models can modify disease progression with significant increase in amyloid-β (Aβ) plaque deposition (Kang et al., 2009).

Whereas this disconnect between amyloid pathology and AD progression implies that other cardinal features of the disease are regulated by sleep disruption, no studies have been published investigating the direct effect of SD on tau metabolism and cognition in transgenic models of AD.

In the present study, we investigated how SD impacts crucial pathways that lead to the development of the full spectrum of the AD phenotype. To this end, we used a transgenic mouse model of AD with plaques and tangle, the 3xTg mouse, and studied the pathologic and behavioral effects of chronic SD. At the end of the study, we found that 3xTg mice that underwent SD developed significant cognitive impairments, altered tau metabolism, and synaptic pathology.

Section snippets

Animals

All animal procedures were approved by the Temple Animal Care and Usage Committee and were in accordance with the institutional and National Institute of Health guidelines. The 3xTg mice harboring a mutant amyloid precursor protein (KM670/671NL), a human mutant PS1 (M146V0) knockin, and tau (P301L) transgenes were used in this study. A total of 18 mice were kept in a pathogen-free environment, on a 12-hour light and/or dark cycle and had access to food and water ad libitum. Starting at the age

Sleep deprived 3xTg mice display irregular sleep-wake cycle

The sleep-wake cycle was recorded using the locomotor cage, which monitors the ambulatory activity of the animals for 24 hours. Confirming the interruption of their regular circadian activities, sleep deprived animals showed a significantly higher ambulatory activity between 15 and 20 hours, which corresponds respectively to 1:00 AM and 6:00 AM, when compared with controls (Fig. 1).

Sleep deprivation effect on cognition

To assess the effect of SD on cognition, mice were initially tested in the Y-maze. As shown in Fig. 2A, we did not

Discussion

In this study, we provide experimental evidence that disruption of the sleep-wake cycle in a mouse model of AD with plaques and tangles results in significant memory impairments, altered tau metabolism, and synaptic pathology. In recent years, emerging data clearly support a relationship between sleep loss, cognitive performance, and neurodegeneration. Interestingly, a recent report showed that regular sleep drives metabolite clearance from the central nervous system, whereas SD impairs it,

Disclosure statement

All authors report no actual or potential conflicts of interest.

Acknowledgements

The authors thank Dr Peter Davis for the generous gift of the PHF-1 and MC1 antibodies used in the study. This work was in part supported by a grant from the Alzheimer's Art Quilt Initiative. The authors are thankful to Dr Ellen Unterwalt for making available to us the motor cages used in this study, Dr Jin Chu and Mrs Elisabetta Lauretti for technical support with the cdk-5 activity assay.

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