Chronic sleep deprivation altered the expression of circadian clock genes and aggravated Alzheimer's disease neuropathology

Abstract Background: Sleep loss leads to a spectrum of mood disorders such as anxiety, cognitive dysfunction and motor coordination impairment in many individuals. However, the underlying mechanisms are largely unknown. Methods: In this study, we examined the effects of sleep deprivation (SD) on depression and the mechanism by subjecting rats to a slowly rotating platform for 3 days to mimic the process of sleep loss. Sleep-deprived animals were tested behaviorally for anxiety- and depressive-like behaviors. We further studied the effects of SD on hypothalamic-pituitary-adrenal (HPA) axis activity, and at the end of the experiment, brains were collected to measure the circadian clock genes expression in the hypothalamus, glial cell activation and inflammatory cytokine alterations. Results: Our results indicated that SD for 3 days resulted in anxiety- and depressive-like behaviors. SD exaggerated cortisol response to HPA axis, significantly altered the mRNA profile of circadian clock genes, and induced neuroinflammation by increasing the expression of glial cell markers, including the microglial marker ionized calcium-binding adapter molecule 1 (Iba1) and the astroglial marker glial fibrillary acidic protein (GFAP). The expression of M1 and M2 microglial markers (Arg-1 and CD206, respectively) and pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) were increased in the brain. Conclusion: These results indicated that SD for 3 days induced anxiety- and depression-like behaviors in rats by impairing the regulation of circadian clock genes and inducing neuroinflammation, ultimately resulting in brain injury.

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Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-2284 ◽

2015 ◽

Vol 100 (9) ◽

pp. E1255-E1261 ◽

Cited By ~ 79

Author(s):

Jonathan Cedernaes ◽

Megan E. Osler ◽

Sarah Voisin ◽

Jan-Erik Broman ◽

Heike Vogel ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Sleep Deprivation ◽

Circadian Clock ◽

Shift Work ◽

Plasma Glucose ◽

Clock Genes ◽

Serum Cortisol ◽

Circadian Clock Genes

Context: Shift workers are at increased risk of metabolic morbidities. Clock genes are known to regulate metabolic processes in peripheral tissues, eg, glucose oxidation. Objective: This study aimed to investigate how clock genes are affected at the epigenetic and transcriptional level in peripheral human tissues following acute total sleep deprivation (TSD), mimicking shift work with extended wakefulness. Intervention: In a randomized, two-period, two-condition, crossover clinical study, 15 healthy men underwent two experimental sessions: x sleep (2230–0700 h) and overnight wakefulness. On the subsequent morning, serum cortisol was measured, followed by skeletal muscle and subcutaneous adipose tissue biopsies for DNA methylation and gene expression analyses of core clock genes (BMAL1, CLOCK, CRY1, PER1). Finally, baseline and 2-h post-oral glucose load plasma glucose concentrations were determined. Main Outcome Measures: In adipose tissue, acute sleep deprivation vs sleep increased methylation in the promoter of CRY1 (+4%; P = .026) and in two promoter-interacting enhancer regions of PER1 (+15%; P = .036; +9%; P = .026). In skeletal muscle, TSD vs sleep decreased gene expression of BMAL1 (−18%; P = .033) and CRY1 (−22%; P = .047). Concentrations of serum cortisol, which can reset peripheral tissue clocks, were decreased (2449 ± 932 vs 3178 ± 723 nmol/L; P = .039), whereas postprandial plasma glucose concentrations were elevated after TSD (7.77 ± 1.63 vs 6.59 ± 1.32 mmol/L; P = .011). Conclusions: Our findings demonstrate that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues. Tissue-specific clock alterations could explain why shift work may disrupt metabolic integrity as observed herein.

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Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer’s disease and longevity in an Italian population

GeroScience ◽

10.1007/s11357-021-00477-0 ◽

2021 ◽

Author(s):

Maria Giulia Bacalini ◽

Flavia Palombo ◽

Paolo Garagnani ◽

Cristina Giuliani ◽

Claudio Fiorini ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Rhythm ◽

Circadian Rhythms ◽

Circadian Clock ◽

Successful Aging ◽

Clock Genes ◽

Association Studies ◽

Italian Population ◽

Age Related

AbstractMany physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

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The Rhythmicity of Clock Genes is Disrupted in the Choroid Plexus of the APP/PS1 Mouse Model of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-200331 ◽

2020 ◽

Vol 77 (2) ◽

pp. 795-806 ◽

Cited By ~ 1

Author(s):

André Furtado ◽

Rosario Astaburuaga ◽

Ana Costa ◽

Ana C. Duarte ◽

Isabel Gonçalves ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Rhythm ◽

Circadian Clock ◽

Choroid Plexus ◽

Clock Genes ◽

Amyloid Β ◽

Model Of Alzheimer’S Disease ◽

Pre Treatment

Background: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. Objective: The fact that circadian rhythm disruption is closely associated to Alzheimer’s disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. Methods: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before amyloid-β stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. Results: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2) expression in male mice. In addition, a significant circadian pattern of Bmal1 was measured the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. Conclusion: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment.

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Circadian Clock Genes and the Transcriptional Architecture of the Clock Mechanism

Endocrine Abstracts ◽

10.1530/endoabs.59.pl4 ◽

2018 ◽

Cited By ~ 1

Author(s):

Joseph Takahashi

Keyword(s):

Circadian Clock ◽

Clock Genes ◽

Circadian Clock Genes ◽

Clock Mechanism

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Transcriptomal dissection of soybean circadian rhythmicity in two geographically, phenotypically and genetically distinct cultivars

BMC Genomics ◽

10.1186/s12864-021-07869-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yanlei Yue ◽

Ze Jiang ◽

Enoch Sapey ◽

Tingting Wu ◽

Shi Sun ◽

...

Keyword(s):

Gene Expression ◽

Circadian Clock ◽

Chromosome Structure ◽

Clock Genes ◽

Expression Profiles ◽

Circadian Rhythmicity ◽

Rna Seq ◽

Night Time ◽

Time Points ◽

Circadian Clock Genes

Abstract Background In soybean, some circadian clock genes have been identified as loci for maturity traits. However, the effects of these genes on soybean circadian rhythmicity and their impacts on maturity are unclear. Results We used two geographically, phenotypically and genetically distinct cultivars, conventional juvenile Zhonghuang 24 (with functional J/GmELF3a, a homolog of the circadian clock indispensable component EARLY FLOWERING 3) and long juvenile Huaxia 3 (with dysfunctional j/Gmelf3a) to dissect the soybean circadian clock with time-series transcriptomal RNA-Seq analysis of unifoliate leaves on a day scale. The results showed that several known circadian clock components, including RVE1, GI, LUX and TOC1, phase differently in soybean than in Arabidopsis, demonstrating that the soybean circadian clock is obviously different from the canonical model in Arabidopsis. In contrast to the observation that ELF3 dysfunction results in clock arrhythmia in Arabidopsis, the circadian clock is conserved in soybean regardless of the functional status of J/GmELF3a. Soybean exhibits a circadian rhythmicity in both gene expression and alternative splicing. Genes can be grouped into six clusters, C1-C6, with different expression profiles. Many more genes are grouped into the night clusters (C4-C6) than in the day cluster (C2), showing that night is essential for gene expression and regulation. Moreover, soybean chromosomes are activated with a circadian rhythmicity, indicating that high-order chromosome structure might impact circadian rhythmicity. Interestingly, night time points were clustered in one group, while day time points were separated into two groups, morning and afternoon, demonstrating that morning and afternoon are representative of different environments for soybean growth and development. However, no genes were consistently differentially expressed over different time-points, indicating that it is necessary to perform a circadian rhythmicity analysis to more thoroughly dissect the function of a gene. Moreover, the analysis of the circadian rhythmicity of the GmFT family showed that GmELF3a might phase- and amplitude-modulate the GmFT family to regulate the juvenility and maturity traits of soybean. Conclusions These results and the resultant RNA-seq data should be helpful in understanding the soybean circadian clock and elucidating the connection between the circadian clock and soybean maturity.

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