Circadian Rhythm Disruption and Alzheimer’s Disease: The Dynamics of a Vicious Cycle

: All mammalian cells exhibit circadian rhythm in cellular metabolism and energetics. Autonomous cellular clocks are modulated by various pathways that are essential for robust time keeping. In addition to the canonical transcriptional translational feedback loop, several new pathways of circadian timekeeping - non-transcriptional oscillations, post-translational modifications, epigenetics and cellular signaling in the circadian clock - have been identified. The physiology of circadian rhythm is expansive, and its link to the neurodegeneration is multifactorial. Circadian rhythm disruption is prevelant in contamporary society where light-noise, shift-work, and transmeridian travel are commonplace, and is also reported from the early stages of Alzheimer's disease (AD). Circadian alignment by bright light therapy in conjunction with chronobiotics is beneficial for treating sundowning syndrome and other cognitive symptoms in advanced AD patients. We performed a comprehensive analysis of the clinical and translational reports to review the physiology of the circadian clock, delineate its dysfunction in AD, and unravel the dynamics of the vicious cycle between two pathologies. The review delineates the role of putative targets like clock proteins PER, CLOCK, BMAL1, ROR, and clock-controlled proteins like AVP, SIRT1, FOXO, and PK2 towards future approaches for management of AD. Furthermore, the role of circadian rhythm disruption in aging is delineated.

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A Growing Link between Circadian Rhythms, Type 2 Diabetes Mellitus and Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms23010504 ◽

2022 ◽

Vol 23 (1) ◽

pp. 504

Author(s):

Xuemin Peng ◽

Rongping Fan ◽

Lei Xie ◽

Xiaoli Shi ◽

Kun Dong ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Type 2 Diabetes ◽

Alzheimer's Disease ◽

Type 2 Diabetes Mellitus ◽

Circadian Rhythm ◽

Circadian Rhythms ◽

Light Therapy

Type 2 diabetes mellitus (T2DM) patients are at a higher risk of developing Alzheimer’s disease (AD). Mounting evidence suggests the emerging important role of circadian rhythms in many diseases. Circadian rhythm disruption is considered to contribute to both T2DM and AD. Here, we review the relationship among circadian rhythm disruption, T2DM and AD, and suggest that the occurrence and progression of T2DM and AD may in part be associated with circadian disruption. Then, we summarize the promising therapeutic strategies targeting circadian dysfunction for T2DM and AD, including pharmacological treatment such as melatonin, orexin, and circadian molecules, as well as non-pharmacological treatments like light therapy, feeding behavior, and exercise.

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Circadian Rhythm Disturbances in Patients with Alzheimer's Disease: A Review

International Journal of Alzheimer s Disease ◽

10.4061/2010/716453 ◽

2010 ◽

Vol 2010 ◽

pp. 1-9 ◽

Cited By ~ 34

Author(s):

Dawit A. Weldemichael ◽

George T. Grossberg

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Rhythm ◽

Core Body Temperature ◽

Treatment Options ◽

Biological Clock ◽

Bright Light ◽

Light Therapy ◽

Care Providers ◽

Major Factors

Circadian Rhythm Disturbances (CRDs) affect as many as a quarter of Alzheimer's disease (AD) patients during some stage of their illness. Alterations in the suprachiasmatic nucleus and melatonin secretion are the major factors linked with the cause of CRDs. As a result, the normal physiology of sleep, the biological clock, and core body temperature are affected. This paper systematically discusses some of the causative factors, typical symptoms, and treatment options for CRDs in patients with AD. This paper also emphasizes the implementation of behavioral and environmental therapies before embarking on medications to treat CRDs. Pharmacotherapeutic options are summarized to provide symptomatic benefits for the patient and relieve stress on their families and professional care providers. As of today, there are few studies relative to CRDs in AD. Large randomized trials are warranted to evaluate the effects of treatments such as bright light therapy and engaging activities in the reduction of CRDs in AD patients.

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Decoding the Inter-relationship between Sleep Disorders and Alzheimer’s disease Pathogenesis

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200903161249 ◽

2020 ◽

Vol 19 ◽

Author(s):

Zeba Mueed ◽

Pankaj Kumar Rai ◽

Mohammad A. Kamal ◽

Nitesh Kumar Poddar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sleep Disorders ◽

Sleep Disturbances ◽

Mammalian Target Of Rapamycin ◽

Light Therapy ◽

Paired Helical Filaments ◽

Bidirectional Relationship ◽

Causative Agents

Alzheimer’s disease (AD), characterized by abnormally phosphorylated tau, paired helical filaments (PHFs), neurofibrillary tangles (NFTs), deregulated mammalian target of rapamycin (mTOR), Aβ deposits, is a multifactorial disease with sleep disorders being one of the causative agents. Therefore, we have reviewed the literature and have tried to decode the existence of positive feedback, reciprocal and a bidirectional relationship allying between sleep disturbances and AD. Much light has been thrown on the role of tau pathology and amyloid pathology in sleep pathology and its association with AD pathology. We have also discussed the role of melatonin in regulating sleep disorders and AD. The neuroprotective action of melatonin via inhibiting tau hyperphosphorylation and Aβ deposition has also been pondered upon. Moreover, astrocytes involvement in aggravating AD has also been highlighted in this review. Several therapeutic approaches aimed at improving both sleep disorders and AD have been duly discussed such as administration of antidepressants and antihistamines, immunotherapy, metal chelators, melatonin supplementation, light therapy and physical activity. Despite consistent efforts, the complete etiology concerning sleep disorder and AD is still unclear. Therefore, further research is needed to unravel the mechanism involved and also to develop strategies that may help in obstructing AD in its preclinical stage.

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Orchestration of the circadian clock and its association with Alzheimer's disease: role of endocannabinoid signaling

Ageing Research Reviews ◽

10.1016/j.arr.2021.101533 ◽

2021 ◽

pp. 101533

Author(s):

Deepak Kumar ◽

Ashish Sharma ◽

Rajeev Taliyan ◽

Maiko T. Urmera ◽

Oscar Herrera Calderon ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Clock

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Fiat Lux: The Light Became Therapy. An Overview on the Bright Light Therapy in Alzheimer’s Disease Sleep Disorders

Journal of Alzheimer s Disease ◽

10.3233/jad-200478 ◽

2020 ◽

Vol 77 (1) ◽

pp. 113-125 ◽

Cited By ~ 1

Author(s):

Ilaria Roccaro ◽

Daniela Smirni

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sleep Disorders ◽

Visual Information ◽

Bright Light ◽

Light Therapy ◽

Pharmacological Intervention ◽

Biological Clocks ◽

Bright Light Therapy ◽

Effective Response

Background: A system of photosensitive retinal ganglion cells provides ‘non-visual’ information on the circadian sequences of light to the suprachiasmatic nucleus (SCN), which, as the ‘master clock’, synchronizes the chronobiological mechanisms of all the biological clocks. Damage to SCN structure alters circadian behavioral and hormonal rhythms and interferes with a regular sleep-wake pattern. Several studies have shown that, in aging and in Alzheimer’s disease (AD), circadian rhythms change their synchronization with the environment and behavior loses sync with light. Objective: The current overview aims to examine research studies showing the effect of bright light therapy (BLT) on sleep disorders and sleep-wake patterns in AD. Methods: A literature search was conducted, taking into consideration the relevant studies over the last 20 years. Fifteen studies have been thorough: seven followed an environmental-architectural approach and eight followed a treatment devices approach. Results: Studies agree in considering BLT as a promising non-pharmacological intervention to compensate for circadian rhythm alterations and they support the need for standardized protocols that allow a comparison between multicenter studies. Conclusion: Interestingly, in an attempt to contain the spread of the COVID-19 pandemic, health authorities have forced the population to stay home. Therefore, AD people are not currently able to enjoy exposure to sunlight. It is predictable that they may experience an exacerbation of circadian disturbances and that the BLT can be an effective response to prevent such exacerbation.

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The role of sleep deprivation and circadian rhythm disruption as risk factors of Alzheimer’s disease

Frontiers in Neuroendocrinology ◽

10.1016/j.yfrne.2019.100764 ◽

2019 ◽

Vol 54 ◽

pp. 100764 ◽

Cited By ~ 10

Author(s):

Hao Wu ◽

Sophie Dunnett ◽

Yuen-Shan Ho ◽

Raymond Chuen-Chung Chang

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Rhythm ◽

Sleep Deprivation

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Elevated CLOCK and BMAL1 Contribute to the Impairment of Aerobic Glycolysis from Astrocytes in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21217862 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7862

Author(s):

Ik Dong Yoo ◽

Min Woo Park ◽

Hyeon Woo Cha ◽

Sunmi Yoon ◽

Napissara Boonpraman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Circadian Rhythm ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Over Expression ◽

Protein Levels ◽

Human Astrocytes ◽

Altered Glucose

Altered glucose metabolism has been implicated in the pathogenesis of Alzheimer’s disease (AD). Aerobic glycolysis from astrocytes is a critical metabolic pathway for brain energy metabolism. Disturbances of circadian rhythm have been associated with AD. While the role of circadian locomotor output cycles kaput (CLOCK) and brain muscle ARNT-like1 (BMAL1), the major components in the regulation of circadian rhythm, has been identified in the brain, the mechanism by which CLOCK and BMAL1 regulates the dysfunction of astrocytes in AD remains unclear. Here, we show that the protein levels of CLOCK and BMAL1 are significantly elevated in impaired astrocytes of cerebral cortex from patients with AD. We demonstrate that the over-expression of CLOCK and BMAL1 significantly suppresses aerobic glycolysis and lactate production by the reduction in hexokinase 1 (HK1) and lactate dehydrogenase A (LDHA) protein levels in human astrocytes. Moreover, the elevation of CLOCK and BMAL1 induces functional impairment by the suppression of glial fibrillary acidic protein (GFAP)-positive filaments in human astrocytes. Furthermore, the elevation of CLOCK and BMAL1 promotes cytotoxicity by the activation of caspase-3-dependent apoptosis in human astrocytes. These results suggest that the elevation of CLOCK and BMAL1 contributes to the impairment of astrocytes by inhibition of aerobic glycolysis in AD.

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Melatonin and Sleep Disturbances in Alzheimer’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210804155617 ◽

2021 ◽

Vol 20 ◽

Author(s):

A. H. M. Safayet Ullah Prodhan ◽

Cinzia Cavestro ◽

Mohammad Amjad Kamal ◽

Md Asiful Islam

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sleep Disturbances ◽

Neurodegenerative Disorder ◽

Bright Light ◽

Light Therapy ◽

Reciprocal Relationship ◽

Exogenous Melatonin ◽

Melatonin Administration ◽

Behavioral Memory

: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by sleep, behavioral, memory, and cognitive deteriorations. Sleep disturbance (SD) is a major disease burden in AD which has a reciprocal relationship with AD pathophysiology. It aggravates memory, behavioral, and cognitive complications in AD. Different studies found that melatonin hormone levels reduce even in the pre-clinical stages of AD. Melatonin is the primary sleep-regulating hormone and a potent antioxidant with neuroprotective roles. The decrease in melatonin levels can thus promote SD and AD neuropathology. Exogenous melatonin has the potential to alleviate neuropathology and SD in AD by different mechanisms. Various studies have been conducted so far that assessed the efficacy of exogenous melatonin to treat SD in AD. Though most of the studies suggest that melatonin is useful to ameliorate SD in AD, the remaining studies show opposite results. The timing, dosage, and duration of melatonin administration along with disease condition, genetic, environmental, and some other factors can be responsible for the discrepancies between the studies. More extensive trials with longer durations and higher dosage forms and studies including bright light therapy and melatonin agonists (ramelteon, agomelatine, and tasimelteon) should be performed to determine the efficacy of melatonin to treat SD in AD.

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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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