Ya-Nan Lv
Yu Cui2
Bo Zhang
Shu-Ming Huang- 1Department of Neuroscience, Institute of Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
- 2Department of Veterinary Medicine, School of Animal Science and Technology, Hainan University, Haikou, China
Sleep disorders are a common health problem in modern society. Long-term sleep deficiency increases the risk for Alzheimer's disease. However, the exact mechanisms by which sleep deficiency affects Alzheimer's disease remain unclear. Therefore, we reviewed the relevant studies and investigated the role of sleep deprivation in Alzheimer's disease pathogenesis. Sleep deficiency was found to be associated with oxidative stress, β-amyloid protein deposition, tau hyperphosphorylation, and neuroinflammation, which are known to increase the risk for Alzheimer's disease. In addition, insufficient sleep also increases glucocorticoid levels, decreases brain-derived neurotrophic factor levels, and reduces the number of synapses in the central nervous system. These factors also promote Alzheimer's disease development and progression. The present study showed that a growing body of evidence supports an association between sleep disturbances and Alzheimer's disease. It discusses the role of sleep insufficiency in Alzheimer's disease pathogenesis, which may provide a theoretical basis for effective treatment and prevention strategies.
1. Introduction
Sleep deficiency occurs when the body does not get the required amount of sleep, i.e., insufficient sleep time or poor sleep quality. The earliest research on sleep deficiency can be traced to more than 100 years ago (1). Approximately 38.2% of the general Chinese population has insomnia symptoms (2). Humans store energy during sleep, reverse damages caused while awake, and process information to facilitate learning and memory (3). Sleep deficiency can cause various adverse effects, including reduced reaction time, reduced vigilance, increased perceptual and cognitive distortion, emotional changes, and even neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson (4). Sleep deficiency is a common early symptom of neurodegenerative diseases. Long-term sleep deficiency affects emotions, learning, and memory (5, 6).
AD is an age-related neurodegenerative disease of the central nervous system characterized by progressive cognitive and memory impairment and the loss of general intelligence, including memory, judgment, and abstract thinking (7). The most characteristic pathological changes associated with AD are senile plaques (SPs) formed by the deposition of β-amyloid protein (Aβ), neurofibrillary tangles (NFTs) formed by intracellular aggregation of abnormally phosphorylated tau proteins, loss of neuronal synapses, and reduced numbers of neurons (8).
Recent studies have extensively investigated the effect of sleep deficiency on AD (9). Clinical and animal experiments suggest that chronic sleep insufficiency may increase AD incidence and accelerate its pathogenesis (10). However, the pathophysiological mechanisms by which long-term sleep deficiency promotes AD progression remain unclear. In this study, we reviewed the literature and analyzed relevant studies to determine the mechanisms for AD induced by long-term sleep deficiency.
2. Mechanism of AD caused by sleep deficiency
Studies have shown that long-term insomnia increases the risk for neurodegenerative diseases, including AD (11). Epidemiological investigations have revealed that about 44% of AD patients had sleep disorders and circadian rhythm disorders (12, 13). With increasing age, the circadian rhythm and sleep-wake regulation system of the elderly gradually degenerate, while the regulation function is weakened, which significantly increases the risk of AD (14). A meta-analysis of 27 observational studies showed that the risk for AD increased by 3.78 times with insomnia and that effective insomnia interventions could delay AD progression in about 15% of the patients (15). In addition, studies have shown that non-rapid eye movement (NREM) sleep slow wave activity decreases with increase of Aβ deposition and tau accumulation (16). Roh et al. reported that a normal sleep-wake cycle and diurnal fluctuation of interstitial fluid (ISF) Aβ are present in the brain of APPswe/PS1δE9 mice before Aβ plaque formation. Following plaque formation, the sleep-wake cycle markedly deteriorated and the diurnal fluctuation of ISF Aβ dissipated (17). Therefore, investigating sleep deficiencies could be significant for AD prevention and treatment.
2.1. Sleep deficiency promotes Aβ deposition
Preclinical studies have demonstrated that neurons release Aβ in an activity-dependent manner under physiological conditions, and that brain Aβ levels show diurnal fluctuations; secretion increases when awake and decreases during sleep (18). Compared to high-quality rest, decreased, low-quality or slow-wave sleep increases cortical neuronal activity and Aβ release (19). With continuous Aβ plaque formation in sleep-regulation centers, sleep cycle-related variations in extracellular Aβ levels disappear. This creates a positive feedback loop; insufficient sleep leads to Aβ deposition and Aβ plaques further affect sleep (20). Kang et al. found that ISF Aβ levels were correlated with wakefulness using in vivo microdialysis, and they demonstrated that Aβ levels in the brain increased and plaque deposition potentially increased in both mouse and human sleep disorders (21). Ooms et al. demonstrated that Aβ1-42 levels in the cerebrospinal fluid increased significantly in healthy males during sleep deprivation, and this change was reversed during good sleep at night, suggesting that short-term sleep deprivation increases Aβ levels (22). Studies in transgenic mice have shown that locus coeruleus degeneration and impaired cortical norepinephrine neuron function could increase the inflammatory response, which was related to increased Aβ and memory deficits (23). Mammalian brain control sleep and wakefulness through complex interactions between subcortical neuromodulatory neurons in the brain stem, midbrain, hypothalamus, and basal forebrain, thalamus, and cortex drive behavioral, physiological, and electrocortical sleep/wake states. Locus coeruleus is also a major brain region among the wake-promoting monoaminergic and cholinergic populations (24). It has also been demonstrated that chronic sleep deficiency increases extracellular Aβ concentration in the brains of model animals, while prolonged sleep reduces Aβ plaque formation (25). Hence, sleep contributes to Aβ clearance, while sleep deprivation promotes Aβ deposition, thus forming the characteristic pathological changes of AD.
2.2. Sleep deficiency induces abnormal tau protein phosphorylation
Tau protein is a protein that regulates and maintains microtubule stability. Under normal conditions, the phosphorylation/dephosphorylation level of tau protein is balanced, which promotes microtubule aggregation and maintains its stability (26). Tau hyperphosphorylation leads to its accumulation and formation of pairs of double helix structures (27). In the brains of AD patients, excessive tau phosphorylation and aggregated NFT deposition results in neuronal degeneration and apoptosis (28). NFTs are the primary brain microstructural features of AD. It has been demonstrated that adults with extreme sleep deficiency have increased tau protein levels in the brain and cerebrospinal fluid (29). Evidence from animal models indicates that changes in sleep-wake cycles increase hyperphosphorylated tau protein levels in the brain (30). Holth et al. showed that mouse ISF tau increased ~90% during normal wakefulness vs. sleep and ~100% during sleep deprivation. In humans, tau levels in the cerebrospinal fluid also increased by more than 50% during sleep deprivation. Thus, the sleep-wake cycle regulates tau level in the brain, and sleep deprivation increases cerebral tau and its pathological diffusion (31). It has been reported that sleep deficiency for two consecutive months can lead to >50% increase in insoluble Tau in the brains of AD patients (32). It can be seen that insufficient sleep can lead to increased tau protein levels, thereby increasing the risk of AD. Thus, optimization of sleep-wake cycle is important for the prevention and treatment of AD.
2.3. Sleep deficiency increases oxidative stress in the brain
Oxidative stress refers to an imbalance between oxidation and anti-oxidation in vivo. Oxidative reactions provide an advantage by producing large numbers of oxidation intermediates (33). Studies have shown that sleep deprivation is linked to free radicals production, which induces oxidative stress. Sleep protects the brain by reducing free radical production (34). The oxidative stress response is influenced by sleep deprivation through three mechanisms. First, sleep deprivation causes abnormal energy metabolism and increases the production of reactive oxygen species and other free radicals. Second, it suppresses the antioxidant defense system. Third, sleep deprivation causes endoplasmic reticulum stress, which indirectly causes oxidative stress (35). In a study, the concentration of glutathione was significantly reduced in rat brains after 96 h of rapid eye movement sleep deprivation compared to controls (36). Ramanathan et al. showed that long-term sleep deprivation significantly decreased the antioxidant activity of superoxide dismutase in rat hippocampi and brainstems (37). Studies have also shown that reduced efficiency of the antioxidant system and excessive production of free radicals, including superoxide anion, hydrogen peroxide, and nitric oxide, are involved in AD pathogenesis (38). The positive correlation between amyloid plaque and lipid peroxidation markers, 4-hydroxynonaldehyde and malondialdehyde (MDA), supports this hypothesis (39). Therefore, insufficient sleep may promote AD by increasing oxidative stress in the brain.
2.4. Sleep deficiency induces neuroinflammation
Neuroinflammation occurs in all neurodegenerative diseases and may be involved in their pathogenesis (40). Microglial cells are involved in immune functions and internal environment homeostasis in the brain. Excessive microglial activation releases inflammatory factors and promotes neuroinflammation (41). Long-term sleep deficiency can lead to chronic systemic low-grade inflammation and is associated with various inflammatory diseases (42). In sleep-related studies, limiting the sleep time for healthy participants to 4 h/day for five consecutive days increased plasma interleukin-6 and C-reactive protein levels in most participants (43). This indicates that a non-specific inflammatory response occurs with prolonged sleep deficiency. It was also reported that serum tumor necrosis factor levels decreased during sleep but increased after 2 days of normal sleep, which indicates the regulation inflammatory cytokines by sleep (44). Spangenberg et al. suggested that extracellular Aβ accumulation may cause chronic neuroinflammation in AD and proposed a microglia-mediated chronic neuroinflammation model, which showed that Aβ binds to microglial toll-like receptors during AD development (45). Initial microglial activation develops into chronic inflammation due to continued stimulation, leading to reduced synaptic remodeling and neuronal death (46). Therefore, inflammation is hypothesized to be a biologically plausible pathway linking sleep disturbance and the risk of AD.
2.5. Sleep deficiency increases glucocorticoid levels
Physiological glucocorticoids regulate growth, immunity, and metabolism (47). When the body encounters injury or stress, excessive glucocorticoids can exert negative effects (48). Long-term stress leads to the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis, resulting in a sustained increase in blood glucocorticoid levels (49).
Clinical studies have shown that cortisol levels increase in the early stages of AD (50). Excessive cortisol secretion may promote neuronal loss and accelerate cognitive decline and disease progression. A longitudinal study from Baltimore suggests that elevated cortisol levels may increase the risk for AD in the elderly (51). Animal experiments have shown that long-term sleep deprivation reduces cell proliferation and adult neurogenesis in rat dentate gyri by increasing glucocorticoids (52). Therefore, increased glucocorticoid levels caused by insufficient sleep lead to decreased cell proliferation. It has been reported that HPA axis hyperactivity may be related to chronic insomnia (53) and that sleep interruptions may be caused by increased corticotropin-releasing hormone (54). Studies have also shown that glucocorticoid receptor antagonists improve sleep quality and may be used to treat chronic insomnia by regulating HPA axis activity (55). Glucocorticoid upregulation is also a typical pathological feature of these two conditions.
2.6. Sleep deficiency reduces synaptic plasticity
Synapses form connections between neurons and are essential for information transmission (56). Synaptic plasticity, including structural and functional plasticity, is a primary manifestation of neural plasticity, which reflects the variability in synaptic morphology, function, and number (57). Sleep deficiency reduces synaptic plasticity, which impairs learning and memory and increases the risk of cognitive impairment in insomniac individuals (58). Studies have shown that synaptic astrocytes promote the development and maturation of dendritic spines and regulate synaptic plasticity. Sleep deficiency reduces dendritic spine density by inhibiting hippocampal astrocytes regulation, thereby affecting the normal hippocampal function (59). A recent positron emission tomography imaging study of AD patients found that sleep deprivation significantly reduced hippocampal synaptic density (60). Wang et al. demonstrated that chronic sleep deprivation aggravated hippocampal synaptic plasticity damage in APP/PS1 double transgenic AD model mice (61). Thus, insufficient sleep decreases the number of synapses in AD patients and impairs signal transduction between neurons.
2.7. Sleep deficiency affects brain-derived neurotrophic factor levels
Brain-derived neurotrophic factor (BDNF), a neurotrophic protein synthesized in the brain, promotes neuronal growth, development, survival, and differentiation (62). It is an important regulator of learning and memory (63). BDNF is down-regulated in both AD and sleep deficiency and is, therefore, a common pathological feature.
Synaptic plasticity in p75 neurotrophin receptor gene knock-out mice after sleep deprivation was found to depend on the enhancement of BDNF pathway conduction (64). Increased expression of BDNF, postsynaptic density protein 95, and other synaptic plasticity-related proteins significantly alleviates hippocampal memory and learning disorders caused by sleep deficiency (65). Animal experiments have also shown that the hippocampal BDNF expression increased 24 h after acute sleep deprivation in mice (66). This was consistent with previous studies that reported that short-term sleep deprivation in humans up-regulated BDNF levels (67). In animal experiments, BDNF consumption and loss increased the number and size of cortical amyloid plaques and aggravated the neuropathological changes in AD mice (68). Increased BDNF levels may also reduce abnormal Aβ production (69).
3. Summary
A growing body of evidence has demonstrated a close relationship between sleep deficiency and AD. Sleep deficiency induces and aggravates AD development and progression (15). Sleep insufficiency accelerates Aβ generation and deposition, promotes Tau protein hyperphosphorylation, and causes oxidative stress and inflammation in the nervous system, thereby increasing the risk for AD. It also reduces the number and transmission function of synapses, increases glucocorticoid level, and decreases BDNF levels, which further promotes AD (Figure 1). Therefore, improving sleep quality may be effective in preventing AD progression.
Figure 1. Mechanism summary of sleep deficiency and AD.
Sleep deficiency is increasingly viewed as an early event in the course of AD. Understanding the mechanisms underlying the effect of sleep deficiency on AD has the potential to optimize efforts for the identification of targets for overcoming AD. This review provides a new perspective for future research on AD, it is that, improving sleep may become an effective means to delay or reduce the occurrence of AD. Therefore, it may provide new insights and entry for researchers to prevent and treat AD by improving sleep in basic and clinical research. Given the evidence in the paper that sleep deficiency is associated with several risk factors for AD, further research is needed to explore how to target improvement of sleep as a novel treatment and even a prevention strategy for AD. We believe that further research on the underlying mechanisms for the association of sleep deficiency with AD will bring us new knowledge.
Author contributions
Y-NL wrote the manuscript. YC wrote and revised the manuscript. S-MH and BZ provided critical comments and revised the manuscript. All the authors approved the final draft and agreed to be accountable for all aspects of the work.
Funding
This work was supported by the National Natural Science Foundation of China (No. 81873108), the Excellent Creative Talents Support Program of Heilongjiang University of Chinese Medicine (No. 2018RCQ08), and the Research Foundation of Heilongjiang University of Chinese Medicine (No. 2019BJP02).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Pilcher JJ, Huffcutt AI. Effects of sleep deprivation on performance: a meta-analysis. Sleep. (1996) 19:318–26. doi: 10.1093/sleep/19.4.318
2. Morin CM, LeBlanc M, Daley M, Gregoire JP, Mérette C. Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Med. (2006) 7:123–30. doi: 10.1016/j.sleep.2005.08.008
3. Rasch B, Born J. About sleep's role in memory. Physiol Rev. (2013) 93:681–766. doi: 10.1152/physrev.00032.2012
4. Ownby RL, Peruyera G, Acevedo A, Loewenstein D, Sevush S. Subtypes of sleep problems in patients with Alzheimer disease. Am J Geriatr Psychiatry. (2014) 22:148–56. doi: 10.1016/j.jagp.2012.08.001
5. Klinzing JG, Niethard N, Born J. Mechanisms of systems memory consolidation during sleep. Nat Neurosci. (2019) 22:1598–610. doi: 10.1038/s41593-019-0467-3
6. Spoormaker VI, van den Bout J. Depression and anxiety complaints; relations with sleep disturbances. Eur Psychiatry. (2005) 20:243–5. doi: 10.1016/j.eurpsy.2004.11.006
7. Eratne D, Loi SM, Farrand S, Kelso W, Velakoulis D, Looi JC. Alzheimer's disease: clinical update on epidemiology, pathophysiology and diagnosis. Australas Psychiatry. (2018) 26:347–57. doi: 10.1177/1039856218762308
8. Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. Dialog Clin Neurosci. (2009) 11:111–28. doi: 10.31887/DCNS.2009.11.2/cqiu
9. Peter-Derex L, Yammine P, Bastuji H, Croisile B. Sleep and Alzheimer's disease. Sleep Med Rev. (2015) 19:29–38. doi: 10.1016/j.smrv.2014.03.007
10. Abbott SM, Videnovic A. Chronic sleep disturbance and neural injury: Links to neurodegenerative disease. Nat Sci Sleep. (2016) 8:55–61. doi: 10.2147/NSS.S78947
11. Cedernaes J, Osorio RS, Varga AW, Kam K, Schiöth HB, Benedict C. Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease. Sleep Med Rev. (2017) 31:102–11. doi: 10.1016/j.smrv.2016.02.002
12. Moran M, Lynch CA, Walsh C, Coen R, Coakley D, Lawlor BA. Sleep disturbance in mild to moderate Alzheimer's disease. Sleep Med. (2005) 6:347–52. doi: 10.1016/j.sleep.2004.12.005
13. Anderson KN, Bradley AJ. Sleep disturbance in mental health problems and neurodegenerative disease. Nat Sci Sleep. (2013) 5:61–75. doi: 10.2147/NSS.S34842
14. Singletary KG, Naidoo N. Disease and Degeneration of Aging Neural Systems that Integrate Sleep Drive and Circadian Oscillations. Front Neurol. (2011) 2:66. doi: 10.3389/fneur.2011.00066
15. Bubu OM, Brannick M, Mortimer J, Umasabor-Bubu O, Sebastião YV, Wen Y, et al. Sleep, cognitive impairment, and alzheimer's disease: a systematic review and meta-analysis. Sleep. (2017) 40:zsw032. doi: 10.1093/sleep/zsw032
16. Lucey BP, McCullough A, Landsness EC, Toedebusch CD, McLeland JS, Zaza AM, et al. Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer's disease. Sci Transl Med. (2019) 11:eaau6550. doi: 10.1126/scitranslmed.aau6550
17. Roh JH, Huang Y, Bero AW, Kasten T, Stewart FR, Bateman RJ, et al. Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology. Sci Transl Med. (2012) 4:150ra22. doi: 10.1126/scitranslmed.3004291
18. Lucey BP, Mawuenyega KG, Patterson BW, Elbert DL, Ovod V, Kasten T, et al. Associations between β-Amyloid kinetics and the β-Amyloid diurnal pattern in the central nervous system. JAMA Neurol. (2017) 74:207–15. doi: 10.1001/jamaneurol.2016.4202
19. Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology–a bidirectional relationship. Nat Rev Neurol. (2014) 10:115–9. doi: 10.1038/nrneurol.2013.269
20. Spira AP, Gottesman RF. Sleep disturbance: an emerging opportunity for Alzheimer's disease prevention? Int Psychogeriatr. (2017) 29:529–31. doi: 10.1017/S1041610216002131
21. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. (2009) 326:1005–7. doi: 10.1126/science.1180962
22. Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: A randomized clinical trial. JAMA Neurol. (2014) 71:971–7. doi: 10.1001/jamaneurol.2014.1173
23. Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer's disease. Med Princ Pract. (2015) 24:1–10. doi: 10.1159/000369101
24. Eban-Rothschild A, Appelbaum L, de Lecea L. Neuronal mechanisms for sleep/wake regulation and modulatory drive. Neuropsychopharmacology. (2018) 43:937–52. doi: 10.1038/npp.2017.294
25. Lim MM, Gerstner JR, Holtzman DM. The sleep-wake cycle and Alzheimer's disease: what do we know? Neurodegener Dis Manag. (2014) 4:351–62. doi: 10.2217/nmt.14.33
26. Kadavath H, Hofele RV, Biernat J, Kumar S, Tepper K, Urlaub H, et al. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc Natl Acad Sci U S A. (2015) 112:7501–6. doi: 10.1073/pnas.1504081112
27. Harrison JR, Owen MJ. Alzheimer's disease: the amyloid hypothesis on trial. Br J Psychiatry. (2016) 208:1–3. doi: 10.1192/bjp.bp.115.167569
28. Gao Y, Tan L, Yu JT, Tan L. Tau in Alzheimer's Disease: Mechanisms and therapeutic strategies. Curr Alzheimer Res. (2018) 15:283–300. doi: 10.2174/1567205014666170417111859
29. Barthélemy NR, Liu H, Lu W, Kotzbauer PT, Bateman RJ, Lucey BP. Sleep deprivation affects tau phosphorylation in human cerebrospinal fluid. Ann Neurol. (2020) 87:700–9. doi: 10.1002/ana.25702
30. Di Meco A, Joshi YB, Praticò D. Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer's disease with plaques and tangles. Neurobiol Aging. (2014) 35:1813–20. doi: 10.1016/j.neurobiolaging.2014.02.011
31. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. (2019) 363:880–4. doi: 10.1126/science.aav2546
32. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. (2001) 60:759–67. doi: 10.1093/jnen/60.8.759
33. Sies H. Oxidative stress: a concept in redox biology and medicine. Redox Biol. (2015) 4:180–3. doi: 10.1016/j.redox.2015.01.002
34. Reimund E. The free radical flux theory of sleep. Med Hypotheses. (1994) 43:231–3. doi: 10.1016/0306-9877(94)90071-X
35. Villafuerte G, Miguel-Puga A, Rodríguez EM, Machado S, Manjarrez E, Arias-Carrión O. Sleep deprivation and oxidative stress in animal models: a systematic review. Oxid Med Cell Longev. (2015) 2015:234952. doi: 10.1155/2015/234952
36. Olonode ET, Aderibigbe AO, Adeoluwa OA, Eduviere AT, Ben-Azu B. Morin hydrate mitigates rapid eye movement sleep deprivation-induced neurobehavioural impairments and loss of viable neurons in the hippocampus of mice. Behav Brain Res. (2019) 356:518–25. doi: 10.1016/j.bbr.2017.12.024
37. Ramanathan L, Gulyani S, Nienhuis R, Siegel JM. Sleep deprivation decreases superoxide dismutase activity in rat hippocampus and brainstem. Neuroreport. (2002) 13:1387–90. doi: 10.1097/00001756-200208070-00007
38. Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, et al. Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia. J Neurosci. (2002) 22:3484–92. doi: 10.1523/JNEUROSCI.22-09-03484.2002
39. Massaad CA. Neuronal and vascular oxidative stress in Alzheimer's disease. Curr Neuropharmacol. (2011) 9:662–73. doi: 10.2174/157015911798376244
40. Lyman M, Lloyd DG Ji X, Vizcaychipi MP, Ma D. Neuroinflammation: the role and consequences. Neurosci Res. (2014) 79:1–12. doi: 10.1016/j.neures.2013.10.004
41. Woodburn SC, Bollinger JL, Wohleb ES. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation. (2021) 18:258. doi: 10.1186/s12974-021-02309-6
42. Smagula SF, Stone KL, Redline S, Ancoli-Israel S, Barrett-Connor E, Lane NE, et al. Actigraphy- and polysomnography-measured sleep disturbances, inflammation, and mortality among older men. Psychosom Med. (2016) 78:686–96. doi: 10.1097/PSY.0000000000000312
43. van Leeuwen WM, Lehto M, Karisola P, Lindholm H, Luukkonen R, Sallinen M, et al. Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLoS ONE. (2009) 4:e4589. doi: 10.1371/journal.pone.0004589
44. Dimitrov S, Besedovsky L, Born J, Lange T. Differential acute effects of sleep on spontaneous and stimulated production of tumor necrosis factor in men. Brain Behav Immun. (2015) 47:201–10. doi: 10.1016/j.bbi.2014.11.017
45. Spangenberg EE, Green KN. Inflammation in Alzheimer's disease: Lessons learned from microglia-depletion models. Brain Behav Immun. (2017) 61:1–11. doi: 10.1016/j.bbi.2016.07.003
46. Calsolaro V, Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions. Alzheimers Dement. (2016) 12:719–32. doi: 10.1016/j.jalz.2016.02.010
47. Inagaki N. Clinico-pharmacology of glucocorticoids. Nihon Jibiinkoka Gakkai Kaiho. (2009) 112:405–13. doi: 10.3950/jibiinkoka.112.405
48. Oray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster CS. Long-term side effects of glucocorticoids. Expert Opin Drug Saf. (2016) 15:457–65. doi: 10.1517/14740338.2016.1140743
49. Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation. (2015) 22:6–19. doi: 10.1159/000362736
50. Popp J, Wolfsgruber S, Heuser I, Peters O, Hüll M, Schröder J, et al. Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type. Neurobiol Aging. (2015) 36:601–7. doi: 10.1016/j.neurobiolaging.2014.10.031
51. Ennis GE, An Y, Resnick SM, Ferrucci L, O'Brien RJ, Moffat SD. Long-term cortisol measures predict Alzheimer's disease risk. Neurology. (2017) 88:371–8. doi: 10.1212/WNL.0000000000003537
52. Mirescu C, Peters JD, Noiman L, Gould E. Sleep deprivation inhibits adult neurogenesis in the hippocampus by elevating glucocorticoids. Proc Natl Acad Sci U S A. (2006) 103:19170–5. doi: 10.1073/pnas.0608644103
53. Vgontzas AN, Bixler EO, Lin HM, Prolo P, Mastorakos G, Vela-Bueno A, et al. Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab. (2001) 86:3787–94. doi: 10.1210/jcem.86.8.7778
54. Ehlers CL, Reed TK, Henriksen SJ. Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats. Neuroendocrinology. (1986) 42:467–74. doi: 10.1159/000124489
55. Buckley T, Duggal V, Schatzberg AF. The acute and post-discontinuation effects of a glucocorticoid receptor (GR) antagonist probe on sleep and the HPA axis in chronic insomnia: a pilot study. J Clin Sleep Med. (2008) 4:235–41. doi: 10.5664/jcsm.27186
56. Südhof TC. The cell biology of synapse formation. J Cell Biol. (2021) 220:e202103052. doi: 10.1083/jcb.202103052
57. Finney CA, Shvetcov A, Westbrook RF, Jones NM, Morris MJ. The role of hippocampal estradiol in synaptic plasticity and memory: A systematic review. Front Neuroendocrinol. (2020) 56:100818. doi: 10.1016/j.yfrne.2019.100818
58. Ferini-Strambi L, Galbiati A, Casoni F, Salsone M. Therapy for insomnia and circadian rhythm disorder in Alzheimer disease. Curr Treat Options Neurol. (2020) 22:4. doi: 10.1007/s11940-020-0612-z
59. Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev. (2006) 10:49–62. doi: 10.1016/j.smrv.2005.05.002
60. Chen MK, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin SF, et al. Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. (2018) 75:1215–24. doi: 10.1001/jamaneurol.2018.1836
61. Wang C, Gao WR, Yin J, Wang ZJ Qi JS, Cai HY, et al. Chronic sleep deprivation exacerbates cognitive and synaptic plasticity impairments in APP/PS1 transgenic mice. Behav Brain Res. (2021) 412:113400. doi: 10.1016/j.bbr.2021.113400
62. Song M, Martinowich K, Lee FS. BDNF at the synapse: why location matters. Mol Psychiatry. (2017) 22:1370–5. doi: 10.1038/mp.2017.144
63. Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. (2014) 220:223–50. doi: 10.1007/978-3-642-45106-5_9
64. Chen L, Dong R, Lu Y, Zhou Y, Li K, Zhang Z, et al. MicroRNA-146a protects against cognitive decline induced by surgical trauma by suppressing hippocampal neuroinflammation in mice. Brain Behav Immun. (2019) 78:188–201. doi: 10.1016/j.bbi.2019.01.020
65. Yan T, Sun Y, Xiao F, Wu B, Bi K, He B, et al. Schisandrae Chinensis Fructus inhibits behavioral deficits induced by sleep deprivation and chronic unpredictable mild stress via increased signaling of brain-derived neurotrophic factor. Phytother Res. (2019) 33:3177–90. doi: 10.1002/ptr.6489
66. Giacobbo BL, Corrêa MS, Vedovelli K, de Souza CE, Spitza LM, Gonçalves L, et al. Could BDNF be involved in compensatory mechanisms to maintain cognitive performance despite acute sleep deprivation? An exploratory study Int J Psychophysiol. (2016) 99:96–102. doi: 10.1016/j.ijpsycho.2015.11.008
67. Giese M, Beck J, Brand S, Muheim F, Hemmeter U, Hatzinger M, et al. Fast BDNF serum level increase and diurnal BDNF oscillations are associated with therapeutic response after partial sleep deprivation. J Psychiatr Res. (2014) 59:1–7. doi: 10.1016/j.jpsychires.2014.09.005
68. Rohe M, Synowitz M, Glass R, Paul SM, Nykjaer A, Willnow TE. Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci. (2009) 29:15472–8. doi: 10.1523/JNEUROSCI.3960-09.2009
69. de Pins B, Cifuentes-Díaz C, Farah AT, López-Molina L, Montalban E, Sancho-Balsells A, et al. Conditional BDNF delivery from astrocytes rescues memory deficits, spine density, and synaptic properties in the 5xFAD mouse model of Alzheimer disease. J Neurosci. (2019) 39:2441–58. doi: 10.1523/JNEUROSCI.2121-18.2019
Keywords: sleep deficiency, Alzheimer's disease, β-amyloid protein, tau protein, oxidative stress, inflammatory response, glucocorticoid, BDNF
Citation: Lv Y-N, Cui Y, Zhang B and Huang S-M (2022) Sleep deficiency promotes Alzheimer's disease development and progression. Front. Neurol. 13:1053942. doi: 10.3389/fneur.2022.1053942
Received: 26 September 2022; Accepted: 30 November 2022;
Published: 14 December 2022.
Edited by:
Ulrich Lothar Maria Eisel, University of Groningen, NetherlandsReviewed by:
Chanung Wang, Washington University in St. Louis, United StatesShen Ning, Boston University, United States
Copyright © 2022 Lv, Cui, Zhang and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Bo Zhang, hljzyyzb@163.com