Mechanisms linking circadian clocks, sleep, and neurodegeneration

Musiek, Erik S.; Holtzman, David M.

doi:10.1126/science.aah4968

Cited by 616 publications

(542 citation statements)

References 97 publications

(117 reference statements)

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“…OSA and chronic obstructive pulmonary disease could contribute to AD processes via hypoxia, inflammation, or sleep disruption 124 . Sleep disruption has been suggested to increase Aβ production and aggregation, suppress glymphatic clearance of AD pathogenic proteins (tau as well as Aβ) and aggravate oxidative stress, inflammation and synaptic damage 125,126 .…”

Section: Respiratory and Sleep Disordersmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Respiratory and Sleep Disordersmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…Mechanisms linking circadian clocks, sleep and neurodegeneration have recently been demonstrated (Musiek and Holtzman, 2016). The presence of insomnia is significantly associated with AD [odds ratio (OR) = 3.32, 95% CI = 1.33–8.28] (Osorio et al, 2011).…”

Section: Melatonin In the Treatment Of Circadian Rhythm And Sleep Dismentioning

confidence: 99%

“…The presence of sleep disorders increases the risk of future cognitive decline in normal older adults (Osorio et al, 2011; Lim et al, 2013) and faster cognitive deterioration in AD patients, suggesting a bidirectional relationship between sleep and AD (Miyata et al, 2013; Spira and Gottesman, 2017). Sleep disruption, especially the reduction in SWS and or increased wakefulness may suppress the function of the glymphatic system that could result in a decreased clearance of pathogenic proteins such as Aβ, which in turn may result in Aβ accumulation and the development of the symptoms of Alzheimer's disease (Musiek and Holtzman, 2016). …”

Section: Melatonin In the Treatment Of Circadian Rhythm And Sleep Dismentioning

confidence: 99%

“…Proposed effects of melatonin on mechanisms linking circadian clocks, sleep and neurodegeneration in AD (adapted from Landry and Liu‐Ambrose, 2014; Musiek and Holtzman, 2016). Sleep–wake and circadian disruption may precede neurodegeneration and the development of cognitive symptoms.…”

Section: Melatonin In the Treatment Of Circadian Rhythm And Sleep Dismentioning

confidence: 99%

“…Sleep is an orchestrated neurochemical process involving sleep‐promoting and arousal centres in the brain (Saper et al, 2005). Sleep has a major role in the restoration of brain energy, in the switching off of external inputs and off‐line processing of information acquired during wake, in the facilitation of the plasticity of cerebral changes that underlie learning, memory consolidation and extinction, and in the activation of the recently discovered glymphatic system that is responsible for brain metabolite clearance (Musiek and Holtzman, 2016). These functions are critical for brain development, physical and mental health, and the maintenance of cognitive functions culminating in a sense of well‐being and daytime vigilance.…”

Section: Introductionmentioning

confidence: 99%

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New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation

Zisapel

2018

British J Pharmacology

567

350

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In mammals, a central circadian clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, tunes the innate circadian physiological rhythms to the ambient 24 h light–dark cycle to invigorate and optimize the internal temporal order. The SCN‐activated, light‐inhibited production of melatonin conveys the message of darkness to the clock and induces night‐state physiological functions, for example, sleep/wake blood pressure and metabolism. Clinically meaningful effects of melatonin treatment have been demonstrated in placebo‐controlled trials in humans, particularly in disorders associated with diminished or misaligned melatonin rhythms, for example, circadian rhythm‐related sleep disorders, jet lag and shift work, insomnia in children with neurodevelopmental disorders, poor (non‐restorative) sleep quality, non‐dipping nocturnal blood pressure (nocturnal hypertension) and Alzheimer's disease (AD). The diminished production of melatonin at the very early stages of AD, the role of melatonin in the restorative value of sleep (perceived sleep quality) and its sleep‐anticipating effects resulting in attenuated activation of certain brain networks are gaining a new perspective as the role of poor sleep quality in the build‐up of β amyloid, particularly in the precuneus, is unravelled. As a result of the recently discovered relationship between circadian clock, sleep and neurodegeneration, new prospects of using melatonin for early intervention, to promote healthy physical and mental ageing, are of prime interest in view of the emerging link to the aetiology of Alzheimer's disease.Linked ArticlesThis article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc

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Association of Sleep and β-Amyloid Pathology Among Older Cognitively Unimpaired Adults

et al. 2021

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IMPORTANCE Disrupted sleep commonly occurs with progressing neurodegenerative disease. Large, well-characterized neuroimaging studies of cognitively unimpaired adults are warranted to clarify the magnitude and onset of the association between sleep and emerging β-amyloid (Aβ) pathology. OBJECTIVE To evaluate the associations between daytime and nighttime sleep duration with regional Aβ pathology in older cognitively unimpaired adults. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, screening data were collected between April 1, 2014, and December 31, 2017, from healthy, cognitively unimpaired adults 65 to 85 years of age who underwent florbetapir F 18 positron emission tomography (PET), had APOE genotype information, scored between 25 and 30 on the Mini-Mental State Examination, and had a Clinical Dementia Rating of 0 for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. Data analysis was performed from December 1, 2019, to May 10, 2021. EXPOSURES Self-reported daytime and nighttime sleep duration. MAIN OUTCOMES AND MEASURES Regional Aβ pathology, measured by florbetapir PET standardized uptake value ratio. RESULTS Amyloid PET and sleep duration information was acquired on 4425 cognitively unimpaired participants (mean [SD] age, 71.3 [4.7] years; 2628 [59.4%] female; 1509 [34.1%] tested Aβ positive).Each additional hour of nighttime sleep was associated with a 0.005 reduction of global Aβ standardized uptake value ratio (F 1, 4419 = 5.0; P = .03), a 0.009 reduction of medial orbitofrontal Aβ (F 1, 4419 = 17.4; P < .001), and a 0.011 reduction of anterior cingulate Aβ (F 1, 4419 = 15.9; P < .001). When restricting analyses to participants who tested Aβ negative, nighttime sleep was associated with a 0.006 reduction of medial orbitofrontal Aβ (F 1,2910 = 16.9; P < .001) and a 0.005 reduction of anterior cingulate Aβ (F 1,2910 = 7.6; P = .03). Daytime sleep was associated with a 0.013 increase of precuneus Aβ (F 1,2910 = 7.3; P = .03) and a 0.024 increase of posterior cingulate Aβ (F 1,2910 = 14.2; P = .001) in participants who tested Aβ negative. CONCLUSIONS AND RELEVANCEIn this cross-sectional study, the increased risk of Aβ deposition with reduced nighttime sleep duration occurred early, before cognitive impairment or significant Aβ deposition. Daytime sleep may be associated with an increase in risk for early Aβ accumulation and did not appear to be corrective for loss of nighttime sleep, demonstrating a circadian rhythm dependence of sleep in preventing Aβ accumulation. Treatments that improve sleep may reduce early Aβ accumulation and aid in delaying the onset of cognitive dysfunction associated with early Alzheimer disease.

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Mechanisms linking circadian clocks, sleep, and neurodegeneration

Cited by 616 publications

References 97 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation

Association of Sleep and β-Amyloid Pathology Among Older Cognitively Unimpaired Adults

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