Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia

Kaushal, Navita; Ramesh, Vijay; Gozal, David

doi:10.1152/ajpregu.00025.2012

Cited by 48 publications

(36 citation statements)

References 64 publications

(77 reference statements)

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“…This is consistent with the notion of ApoE ε4 as a causative factor for AD, and supports our findings that ApoE deficiency leads to SCN degeneration and malfunction. In fact, mice expressing the human ApoE ε4 allele were also prone to develop sleep disruption and intermittent hypoxia35. These findings, together with our results, strongly suggest that abnormal ApoE expressions seen in the familial and sporadic AD result in CRDs.…”

Section: Discussionsupporting

confidence: 81%

Degeneration and energy shortage in the suprachiasmatic nucleus underlies the circadian rhythm disturbance in ApoE−/− mice: implications for Alzheimer’s disease

Zhou

Gao

Nie

et al. 2016

Sci Rep

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Alzheimer’s disease (AD) patients suffer sleep disorders and circadian rhythm disturbances (CRDs). The underlying mechanisms are incompletely understood, and treatments are lacking. In this study, we characterized the locomotor activity, clock gene expression, morphological degeneration and energy metabolism of suprachiasmatic nucleus (SCN), together with retinal light sensing, in ApoE−/− mice, a model for AD. Compared with the control C57BL/6J mice, ApoE−/− mice exhibited disordered circadian locomotor activity under dim light and constant darkness, with impaired re-entrainment to phase change schedules. Decreased retinal melanopsin expression, together with amyloidosis and tau deposition, was evident in ApoE−/− mice. Mitochondrial and synaptic deterioration, altered SIRT1-mediated energy metabolism and clock gene expression were also observed in ApoE−/− SCN. Supplementation with fat or ketone bodies but not glucose, or intraperitoneal administration of nicotinamide, restored the locomotor rhythmicity and circadian expression of SIRT1 and clock genes, as well as reducing neurodegeneration. Taken together, ApoE deficiency induced degeneration and a significant disturbance in the SCN rhythmicity. Decline of retinal light sensing and SCN structural and metabolic deteriorations represented the major pathologies accounting for the CRDs in ApoE−/− mice. Our curative experiments may help develop future therapies to treat the CRDs and sleep disorders in AD patients.

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Section: Discussionsupporting

confidence: 81%

Degeneration and energy shortage in the suprachiasmatic nucleus underlies the circadian rhythm disturbance in ApoE−/− mice: implications for Alzheimer’s disease

Zhou

Gao

Nie

et al. 2016

Sci Rep

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“…The custom-designed sleep fragmentation approach used to induce SF in rodents has been previously reported in detail (29, 33), and relies on automated intermittent tactile stimulation of freely behaving mice in a standard laboratory mouse cage, using a near-silent motorized mechanical sweeper. This method obviates the need for human contact and intervention, and does not involve introduction of foreign objects or touching of the animals during sleep.…”

Section: Methodsmentioning

confidence: 99%

Fragmented Sleep Accelerates Tumor Growth and Progression through Recruitment of Tumor-Associated Macrophages and TLR4 Signaling

et al. 2014

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Fragmented sleep (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that SF promotes tumor growth and progression through pro-inflammatory TLR4 signaling. In the design, we compared mice that were exposed to SF one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis three weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that SF enhanced tumor size and weight compared to control mice. Increased invasiveness was apparent in SF tumors, which penetrated the tumor capsule into surrounding tissues including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in SF tumors where they were distributed in a relatively closer proximity to the tumor capsule, compared to control mice. Although tumors were generally smaller in both MYD88−/− and TRIF−/− hosts, the more aggressive features produced by SF persisted. In contrast, these more aggressive features produced by SF were abolished completely in TLR4−/− mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways.

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“…Moreover, the degree of sleep disruption that might be present due to underlying sleep disorders, e.g., OSAS, or be environmentally induced by sleep disruptors such as traffic noise has not been specifically addressed. To explore the potential implications of SFon tumor proliferation and invasiveness, we exposed mice to a now extensively validated paradigm of disrupted sleep (SF) whereby mice undergo periodic arousals during their sleep period (45–48). Although SF exposures do not induce increases, of circulating levels of corticosterone suggesting that they are relatively non-stressful, we have not specifically examined to date whether SF alters systemic and tissue levels of catecholamines.…”

Section: Introductionmentioning

confidence: 99%

Obstructive sleep apnea and cancer: Epidemiologic links and theoretical biological constructs

Gozal

Farré

Nieto

2016

Sleep Medicine Reviews

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101

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SUMMARY Sleep disorders have emerged as highly prevalent conditions in the last 50–75 years. Along with improved understanding of such disorders, the realization that perturbations in sleep architecture and continuity may initiate, exacerbate or modulate the phenotypic expression of multiple diseases including cancer has gained increased attention. Furthermore, the intermittent hypoxia that is attendant to sleep disordered breathing, has recently been implicated in increased incidence and more adverse prognosis of cancer. The unifying conceptual framework linking these associations proposes that increased sympathetic activity and/or alterations in immune function, particularly affecting innate immune cellular populations, underlie the deleterious effects of sleep disorders on tumor biology. In this review, the epidemiological evidence linking disrupted sleep and intermittent hypoxia to oncological outcomes, and the potential biological underpinnings of such associations as illustrated by experimental murine models will be critically appraised. The overarching conclusion appears supportive in the formulation of an hypothetical framework, in which fragmented sleep and intermittent hypoxia may promote changes in multiple signalosomes and transcription factors that can not only initiate malignant transformation, but will also alter the tumor microenvironment, disrupt immunosurveillance, and thus hasten tumor proliferation and increase local and metastatic invasion. Future bench-based experimental studies as well as carefully conducted and controlled clinical epidemiological studies appear justified for further exploration of these hypotheses.

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Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia

Abstract: Kaushal N, Ramesh V, Gozal D. Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia.

Cited by 48 publications

References 64 publications

Degeneration and energy shortage in the suprachiasmatic nucleus underlies the circadian rhythm disturbance in ApoE−/− mice: implications for Alzheimer’s disease

Degeneration and energy shortage in the suprachiasmatic nucleus underlies the circadian rhythm disturbance in ApoE−/− mice: implications for Alzheimer’s disease

Fragmented Sleep Accelerates Tumor Growth and Progression through Recruitment of Tumor-Associated Macrophages and TLR4 Signaling

Obstructive sleep apnea and cancer: Epidemiologic links and theoretical biological constructs

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