The Effect of Insomnia On Development of Alzheimer 'S Disease

Sadeghmousavi et al.
Journal of Neuroinflammation (2020) 17:289

https://doi.org/10.1186/s12974-020-01960-9
REVIEW Open Access
The effect of insomnia on development of

Alzheimer’s disease
Shaghayegh Sadeghmousavi1,2, Mahsa Eskian1,3,4, Farzaneh Rahmani1,3,5 and Nima Rezaei1,3,4,6*
Abstract
Alzheimer’s disease (AD) is the most common type of dementia and a neurodegenerative disorder characterized by
memory deficits especially forgetting recent information, recall ability impairment, and loss of time tracking,
problem-solving, language, and recognition difficulties. AD is also a globally important health issue but despite all
scientific efforts, the treatment of AD is still a challenge. Sleep has important roles in learning and memory
consolidation. Studies have shown that sleep deprivation (SD) and insomnia are associated with the pathogenesis
of Alzheimer’s disease and may have an impact on the symptoms and development. Thus, sleep disorders have
decisive effects on AD; this association deserves more attention in research, diagnostics, and treatment, and
knowing this relation also can help to prevent AD through screening and proper management of sleep disorders.
This study aimed to show the potential role of SD and insomnia in the pathogenesis and progression of AD.
Keywords: Alzheimer’s disease, Sleep, Sleep deprivation, Insomnia, Inflammatory processes
Introduction AD is a progressive neurodegenerative disorder char-

Dementia is one of the major causes of disability and acterized by cognitive and non-cognitive disabilities [6].
mortality and a common disease in the elderly [1]. It is Symptoms vary among people with AD based on the de-
characterized by difficulties with memory, language, gree of damage to neurons in different parts of the brain.
problem-solving, and a decline in cognitive level, which The common symptoms of AD are memory deficits es-
affects daily routine and social activities [2]. Dementia pecially forgetting recent information, recall ability im-
has different types including Alzheimer’s disease, vascu- pairment, loss of time tracking, and problem-solving,
lar dementia, dementia with Lewy bodies (DLB), mixed language, and recognition difficulties [3, 7–9]. Accumu-
dementia, frontotemporal lobar degeneration (FTLD), lation of extracellular amyloid-beta (Aβ) plaques is a
and Parkinson’s disease (PD) dementia [3]. considerable pathological event in AD, along with ele-
Alzheimer’s disease is the most common type of de- vated intraneuronal tau expression and age-related de-
mentia [3, 4]. Based on the World Health Organization’s position of intracellular tau as neurofibrillary tangles
(WHO) reports, nearly 50 million people have dementia which occurs concomitantly with Aβ deposition in a
worldwide. There are about 10 million new cases annu- mutually exacerbating manner [10–12].
ally and Alzheimer’s disease (AD) may contribute to 60– Neuroinflammation is also a major element in AD
70% of the cases [5]. pathogenesis, initiated by and precipitating both Aβ and
tau deposition [13–15]. The neuroinflammatory re-
sponse in AD entails a complex response from recruit-
* Correspondence: [email protected] ment of peripheral immune cells including leukocytes
1
Neuroimaging Network (NIN), Universal Scientific Education and Research and T cells, glial cell activation, induction of intracellular
Network (USERN), Tehran, Iran
3
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, signaling pathways, and release of inflammatory media-
Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran tors including interleukin-1 (IL-1), interleukin-6 (IL-6),
Full list of author information is available at the end of the article
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Sadeghmousavi et al. Journal of Neuroinflammation (2020) 17:289 Page 2 of 20
interleukin-18 (IL-18), tumor necrosis factor-α (TNF-α), levels in the early evening, and their lowest blood levels
interferons (IFN) and interleukin-12 (IL-12). These cyto- in the morning [44]. Sleep disturbance disrupts this
kines are upregulated in signature AD regions and result regulation through increasing levels of proinflammatory
in neuronal dysfunction or death [16–19]. cytokines such as IL-6, TNF-α, and IL-1, and CRP levels
Normal sleep has been reported to contribute to tissue [45, 46]. Indeed, sleep duration is directly correlated
repair, thermoregulation, homeostatic restoration, mem- with lower levels of inflammatory markers [47–50], and
ory consolidation processes, and preservation of hence with a predisposition to AD.
neuroimmune-endocrine integrity [20, 21]. Because of the fast-growing number of patients with
During sleep, the brain switches periodically between dementia, particularly AD, and the fact that despite all
different activity states which are non-rapid eye move- scientific efforts, at the moment treatment is not a feas-
ment (NREM) sleep and rapid eye movement (REM) ible option for this disease, since insomnia is a manage-
sleep [22]. REM sleep is considered important for learn- able and preventable disorder, understanding the role of
ing, memory consolidation, neurogenesis, and regulation insomnia in AD may lead to prevention or treatment op-
of the blood-brain barrier function [23–25], while non- portunities for AD.
REM sleep has been related to the regulation of hormo- Based on the studies, the major pathological agent in
nal release, the lowering of the thermal set point, and is AD is Aβ. It has been reported that insomnia can cause
characterized by a reduction of cardiovascular parame- a rise in the CSF levels of Aβ [51].
ters such as blood pressure [20, 26]. Sleep deprivation and insomnia can induce aggregation
Sleep disorders can cause stress, somatic and psycho- of Aβ peptides and tau proteins, the two hallmark patho-
social issues, including anxiety, depression, memory logical features of Alzheimer’s disease (AD) [52–54]. In
problems, chronic diseases such as cardiovascular dis- light of this and several other findings, we aim to elucidate
ease, hypertension, diabetes and cancer, reduced quality the potential role of SD and insomnia in the pathogenesis
of life, and increased mortality. Also, their other impacts and progression of AD (see Fig. 1).
are difficulties with work, increased accidents, and hav-
ing economic burden [27–29]. Sleep disorders are pre- Beta-amyloid
vailing due to changes in western lifestyle [30] so that Amyloid peptides are 39 to 43 residue proteolytic prod-
their prevalence in the USA was announced to be about ucts [55] which are formed through cleavage of the
70 million (based on the Institute of Medicine, Commit- amyloid precursor protein (APP) by β and γ-secretases.
tee on Sleep Medicine & Research 2006) [31]. Among Accumulation of Aβ is a major cause of synaptic dys-
sleep disorders, insomnia has the most prevalence in function and impairment of neurotransmission, which is
adults. The estimated prevalence of difficulty in initiating critical to the pathogenesis of AD [56]. Accumulation of
and maintaining sleep is about 30% [32]. Aβ is the result of an imbalance between its production
Insomnia is a sleep disorder in which patients have and clearance [57]. Intraneuronal Aβ accumulation is an
dissatisfaction with sleep quality or duration, difficulty in early event in AD, resulting from cleavage of the APP at
falling asleep at night, or waking up too early in the the beta cleavage site [58].
morning and it can lead to daytime fatigue, low energy, β-site APP-cleaving enzyme I (BACE1) is responsible
difficulty in maintaining attention, and formation of for the Aβ accumulation. APP is a protein located in the
long-term memory [33–35]. Insomnia is frequently asso- plasma membrane that is concentrated at neuronal
ciated with neuropsychiatric comorbidities like anxiety, synapses [57, 59], the Golgi network, endoplasmic
depression, substance use disorder, and comorbidity reticulum (ER), and endosomal, lysosomal, and mito-
with other disorders like the presence of pain and psy- chondrial membrane [59–61]. It has roles in cell adhe-
chiatric disorders [36] and also, adults with insomnia are sion and movement [62, 63]. Aβ is predominantly
at great risk of hypertension, type 2 diabetes, neurocog- produced as a monomer, and then aggregates and forms
nitive disorders, depression, and mortality [37–39]. multimeric complexes [64] at the plasma membrane
Acute insomnia is defined as any of the mentioned where β- and γ-secretases are at their highest concentra-
symptoms occurring for less than 4 weeks, which usually tion [65]. The oligomeric species of Aβ are the most
resolves with discontinuation of the causal stressor [40]. pathological components and can cause hippocampal
Untreated acute insomnia or persistence of the stressor synaptic loss, and failure of long-term potentiation in
can lead to chronic insomnia, which is in association rats [66–68].
with comorbid anxiety and depression [41]. Degeneration of cholinergic neurons, alteration in
The human immune system follows diurnal patterns glutamatergic synaptic transmission, and most import-
like that of the circadian rhythm [42, 43]. Levels of cyto- antly synaptic loss, dendritic spine loss, and cell death
kines and immunoglobulins are highest during the night, are among the neurotoxic effects of amyloid-beta pep-
while immune cells in the blood are at their highest tides [10, 69–72].
Fig. 1 Mechanisms that can link insomnia to the pathogenesis and progression of AD
Intracerebral injection of synthetic Aβ that included a significantly was increased during acute SD, and also
mixture of amyloid-β fibrils, protofibrils, oligomers, and chronic sleep restriction (SR) significantly increased Aβ
monomers deteriorated learning behavior in rats [73, 74]. plaque formation in amyloid precursor protein trans-
Amyloidosis is a clinical disorder that occurs due to the genic mice.
extracellular and/or intracellular deposition of insoluble Human studies such as Hung et al. reported that pa-
pathogenic amyloid built of misfolded proteins [75–78]. tients who have insomnia are at a greater risk of being di-
Cells have well-designed systems including chaperones agnosed with dementia. During the 3-year follow up of 51,
to check that protein folding. In addition to this ensur- 743 primary insomnia patients (older than 20 years of
ing system, there are selective degradation mechanisms age), after adjusting for sex, the region of residence, and
like the proteasome which has a disposing role of the selected comorbidities, a primary insomnia diagnosis was
misfolded proteins. Unlike other misfolded proteins, independently associated with a 2.14-fold (p value < 0.05)
amyloid species can escape from quality control systems higher risk of subsequent development of dementia [96].
such as the ubiquitin-proteasome pathway, due to their Chen et al. suggested the correlation between Aβ levels of
ability to aggregate into fibrillar structures [79]. This fact CSF with the duration of insomnia in 23 patients with
implicates that inhibition of the proteasome pathway, chronic insomnia aged between 46 and 67 and showed
other Aβ degrading enzymes such as β- and γ-secretases long-term poor sleep quality has accumulative effects on
[80, 81], or uptaking to lysosomes or brain vasculature brain Aβ42 levels [51]. It has been suggested that wakeful-
[82–85] can lead to the accumulation of misfolded amy- ness increases neuronal activity, and hence the production
loidogenic proteins and peptides. Different cell types in and secretion of Aβ [97]. Moreover, reduced neuronal ac-
brain parenchyma and vasculature have roles in the cel- tivity during sleep can increase the clearance of Aβ and
lular clearance of Aβ. Cell surface Aβ-binding receptors lower Aβ production [93, 98–100]. Also, the glymphatic
mediate these pathways and apolipoprotein E (apoE) system, which is a waste clearance system that uses peri-
regulates them [86, 87]. vascular tunnels made from astroglial cells, to promote ef-
Several studies demonstrate sleep disturbance and in- ficient removal of soluble proteins and metabolic waste in
somnia are associated with a higher incidence of demen- the CNS, is more active in sleep time compared to wake-
tia [88–92]. Animal models of AD and sleep disturbance fulness [101]. A study in this area by Xie et al. revealed
have been demonstrated that Aβ levels in brain intersti- that radioactively labeled Aβ injected into the cortex of
tial fluid (ISF) and brain tissue remarkably increased in live mice was removed more efficiently during sleep than
mice suffering from sleep deprivation, compared to nor- in awake time [102].
mal mice [52, 93–95]. Chen et al. [52], after inducing SD Based on evidence from animal and human studies, it
in Sprague-Dawley rats, confirmed that SD impaired can be concluded that increasing Amyloid peptides dur-
cognitive function and increased the levels of brain Aβ ing sleep deprivation may be potential pathogenesis of
peptides, and significantly increased the levels of the AD progression. However, more studies are warranted.
BACE1and β-secretase, but had little impact on the
levels of Aβ-degradation enzymes. They mentioned that Tau protein
this result may be the main cause of the over-expression Tau is the major microtubule-associated protein in neu-
of Aβ1-42 and Aβ1-40. Kang et al. [93], by using in vivo rons [103]. Human tau is expressed by the MAPT gene,
microdialysis in mice, found that the amount of ISF Aβ located on chromosome 17 [104]. In the human CNS,
especially in the brain [105], tau protein is translated detected the presence of abundant filaments made of
from an mRNA transcript producing six tau protein iso- hyperphosphorylated tau protein. Dysfunction and death
forms which the amount of them varies in different re- of nerve cells due to mutant tau protein were suggested
gions. For example, in humans, the 0N3R tau is lower in in their study. In another study, SantaCruz et al. [140]
the cerebellum in comparison to other brain regions and suggested that mice with a repressible human tau variant
4R tau isoforms are increased in the Globus pallidus developed progressive age-related NFTs, neuronal loss,
[106–108]. The morphology and integrity of neurons are and behavioral impairments. Argyrophilic tangle like in-
maintained largely by the cytoskeleton, which is partially clusions, brain weight loss, neuron loss, brain atrophy,
composed of microtubules. The main biological func- abnormal accumulation of hyperphosphorylated tau le-
tions of tau are considered to be the stimulation of sions, and impairment of spatial memory developed
microtubule assembly and the reduction of their dy- more as the mice aged so that there were no significant
namic instability [109–111]. In addition to the men- abnormalities during the probe trials in the water maze
tioned roles, it has been suggested that it may have in 1.3-month-old transgenic mice, and the youngest
other physiological functions including interfering with mice showed no major deficits in the retention of spatial
the binding of kinesin and kinesin-like motors to micro- memory but the retention of spatial reference memory
tubules which cause inhibition of plus-end directed declined dramatically in an age-dependent manner. After
axonal transport in the absence of its phosphorylation the suppression of transgenic tau, memory function re-
by glycogen synthase kinase (GSK)-3 [112]. Also, tau has covered, and neuron numbers stabilized, but NFTs con-
interactions with mitochondria [113], plasma membrane tinued to accumulate.
[114], and nucleic acids [115, 116], showing its act as a Several mechanisms have been suggested for the role
mediator between microtubules and these organelles of tau in neurodegeneration including causing the disas-
[103]. Tau is a phosphoprotein that has 2–3 moles of sembly of microtubules [141], compromising the micro-
phosphates per every mole [117, 118]. The phosphoryl- tubule stability and function, resulting in a loss or
ation of tau regulates its binding to microtubules and decline in axonal or dendritic transport in disease [142,
stimulates their assembly. A normal level of phosphoryl- 143], disrupting intracellular compartments such as
ation of tau is required for optimal function, whereas the mitochondria and the endoplasmic reticulum that are
hyperphosphorylated tau impairs its biological activity essential for normal metabolism and alteration of the
[119–122]. Hyperphosphorylation of amino acids in tau distribution of these organelles due to the change in
proteins causes the detachment from the microtubules microtubule-dependent motor proteins [144–146]. It has
which this dissociation is a prerequisite for them to ag- been suggested that there is an inter-relationship be-
gregate, impairment of the axonal transport, starvation tween Aβ and tau and they do not act in isolation [147–
of neurons which leads to cell death and synaptic loss 149] and either of them has a crucial role in synaptotoxi-
[123–126]. Intracellular accumulation of misfolded tau city and neurodegeneration. Some evidence suggests that
leads to a reduction in the cellular burden of aggregated tau pathology can be ameliorated to some extent by Aβ
proteins and also promotes the secretion of tau aggre- immunization which triggers the phosphorylated-tau ag-
gates [127]. Also, tau secretion is a regulatable process, gregation in the neuronal processes [150–153]. Also,
and dysregulation of it can cause the spread of tau path- there is strong evidence that tau is essential for Aβ-
ology [127–129]. Abnormal hyperphosphorylation of tau mediated pathology in animal models of plaque depos-
and its intracellular aggregation in the brains and extra- ition and genetically decreasing endogenous tau is pro-
cellular aggregation in CSF and ISF can be detected in tective against synapse loss [154–156]. Jackson et al.
AD patients and it is considered as the second patho- [157], to examine Aβ-plaque load and synapse loss in
logical hallmark of AD [103, 130–133]. Neurofibrillary the presence of human tau, generated a mouse model of
tangles (NFTs) are intracellular fibrillar structures com- early AD, in which mutant human APP, PS1, and wild-
posed of aggregations of abnormally phosphorylated tau type human tau were co-expressed. They analyzed the
[134, 135]. The number and localization of NFTs, unlike interactions of human tau and Aβ in a mammalian brain
the senile plaques, are associated with the severity of de- with age-related pathology and compared it to the group
mentia [136]. As a leading component in AD pathogen- of mice (8–10 months old) with only APP and PS1 gene
esis, hyperphosphorylated tau is considered as a mutations using western blotting, ELISA, immunohisto-
neurotoxic agent that can lead to neuronal loss [137, chemical analysis, and array topography. They found
138]. Allen et al. [139], studied the neurodegeneration in that over-expressing wild-type human tau increases Aβ-
the transgenic mice expressing isoform of human tau. plaque size and dystrophic neurite number but it did not
According to light microscopy, many nerve cells in the cause Aβ-mediated synaptic loss and neuronal loss,
brain and spinal cord were strongly immunoreactive for while in another study by Umeda et al. [158], wild-type
hyperphosphorylated tau and electron microscopy human tau expressing mice with high levels of human
Aβ oligomers had neurofibrillary tangle pathology devel- mice). Compared with controls, the behavioral assess-
opment and synapse loss at much older ages (18 ment showed that SD-treated (4 h sleep restrain per day
months) which the difference between the result of these for 8 weeks) mice had a significant decline in their learn-
two studies can be due to the different ages examined ing and memory and a significant increase in tau protein
and the role of age in cognitive deficits. insoluble fraction which is associated with tau metabol-
For relating insomnia to the development of AD ism impairment. Another study by Lucey et al. [160], by
through tau pathologies, we reviewed the literature ad- using single-channel EEG with PET imaging and CSF
dressing this issue. analysis of both Aβ and tau in participants enrolled in
Likewise, Aβ neuronal activity can induce the extracel- longitudinal studies of aging, revealed that a decrease in
lular release of tau. Pooler et al. [129] showed that SWS, especially at the lowest frequencies of 1–2 Hz, was
stimulation of neuronal activity results in the release of more associated with the accumulation of tau even more
endogenous tau in an in vitro model by AMPA receptor than that of Aβ. They suggested that changes in NREM
stimulation. They identified that AMPA receptor stimu- SWA might lead to tau pathology and cognitive impair-
lation increased tau release in a dose-dependently man- ment either before or at the earliest stages of symptom-
ner compared with control cells and the amount of atic AD.
extracellular tau was substantially increased. They con- Holth et al. [161] showed that chronic SD increases
cluded that this secreted tau might underlie the propaga- tau acutely over hours and also drives tau pathology
tion of tau pathology in tauopathies. Also, Wu et al. spreading in the brains of mice and humans. In closing,
[159] found that increased neuronal activity enhances they have mentioned that optimization of the sleep-wake
tau pathology in vivo. They optogenetically and chemo- cycle should be considered for the prevention of AD and
genetically stimulated transgenic tau mice and it caused other tauopathies.
robust worsening of pathology and accumulation of cell Together, these studies can explain the impact of in-
body tau in the stimulated hippocampus which appeared somnia on AD development thorough tau pathogenesis
to be neurotoxic, and lead to exacerbated hippocampal and accumulation.
cell layer atrophy but additional pathology in cells such
as the dentate gyrus granule cell layer was not detected. Inflammatory processes
However, in the transgenic mice, tau accumulates slowly Inflammation occurs in the AD brain because of the exist-
in the granule cell layer (more than 18 months to being damage. Based on the prior section, overproduction of
come apparent), so more time may be needed to effect- Aβ is the major cause of the AD pathology although Aβ is
ively induce tau propagation into the granule cells of the detected in both normal and AD brains [162] and this
dentate gyrus and pathology advancement. So based on suggests that Aβ alone may not be enough to cause AD.
the aforementioned studies, we can relate increased Inflammatory proteins have been reported as the potential
neuron stimulation caused by sleep deprivation to tau pathogenesis of AD [163–165]. The AD can predispose
aggregation. the brain toward the occurrence of chronic inflammation
Rothman et al. [94] tested the hypothesis that sleep re- to cause more damage besides the primary pathologic
striction worsens memory impairments, Aβ, and tau ac- events [166]. The inflammatory components that have
cumulations in the brain in a mouse model of AD. They roles in AD pathogenesis are complement pathway, cyto-
established sleep restriction (6 h/day for 6 weeks) in kine and chemokine pathways, cells, cyclooxygenase en-
transgenic AD mice and compared the analysis data of zyme, blood coagulation, and fibrinolysis systems, and
SR and control groups. Behavioral data indicated deficits other acute-phase proteins such as ApoE and free radicals
in contextual and cued memory in SR mice that were [167]. These different mechanisms lead to a vicious cycle
not present in the control group (p < 0.04). Both Aβ and of AD pathogenesis. For example, Aβ accumulations can
tau levels increased in the cortex of SR mice compared directly activate the complement proteins [168], then the
to control. Qiu et al. [95] also demonstrated the exacer- complement proteins can accelerate the aggregation of Aβ
bation of AD due to the chronic sleep deprivation in so it is a bidirectional relationship [169, 170] and as more
AβPP(swe)/PS1(ΔE9) transgenic mice. Mice exposed to Aβ becomes aggregated better, it can activate complement
2-month SD in addition to an altered Aβ precursor pro- component (Clq) [171]. Aβ provokes cytokine production
cessing showed an elevated level of phosphorylated tau [172, 173], in turn cytokine production can lead to stimu-
protein, and impaired cognitive performance as com- lation of Aβ precursor protein production [174]. Further
pared to non-sleep deprivation controls and these Aβ deposition stimulates inflammation consistently.
changes were long-lasting and were irreversible during a Chronic inflammation especially increased levels of C-
3-month normal housing condition. Di Meco et al. [53] reactive protein and IL-6 have been reported as the po-
studied the effect of SD on the development of AD in a tential mechanism of the complications of insomnia [39,
transgenic mouse model with plaques and tangles (3xTg 175–177] same as increased incidence of infectious
diseases, for instance, pneumonia [178], common cold Several studies contest the claim that there is neural-
[179], herpes zoster [180] and HIV [181], inflammatory immune signaling which suggests the possibility of a
diseases such as rheumatoid arthritis [182], heart failure homeostatic feedback loop between sleep and inflamma-
[183], cardiovascular disease [184, 185], and cancer [186, tion. Dantzer et al., in a review study, showed that the
187]. Therefore, insomnia and disturbance of sleep pro- brain can respond to inflammatory stimuli by producing
vide a route to the production of inflammatory media- pro-inflammatory cytokines so, during infection or a
tors [45, 188–191]. So, activation of the inflammatory chronic health problem, the production of the pro-
response links insomnia and dementia risk [192, 193]. In inflammatory cytokines can lead to sickness behavior
human studies, even experimental sleep duration ma- and depression [197]. In another study, Irwin et al.
nipulation leads to increases in inflammatory compo- reviewed the feedback of the innate immune system
nents [175, 194]. Based on Irwin et al.’s studies after a through the production of cytokines to modulate the
night of partial sleep deprivation, activation of upstream brain function [198].
markers of inflammation including activation of inflam- Some studies suggest altered sleep can change the levels
matory signaling pathways such as nuclear factor κB of cytokines which are known to be important in regulat-
(NF-κB), activator protein 1, and STAT family proteins ing inflammation (see Table 1). The first observations
also increase in mRNA expression of other proinflam- which connect sleep deprivation to innate immunity were
matory cytokines [48, 176, 194]. Irwin M.R. et al., by by Moldofsky et al. and showed prolonged sleep loss or 40
assessing the level of intracellular proinflammatory cyto- h of wakefulness of 10 healthy subjects led to elevated
kines three times the day and after partial sleep levels of IL-1-like (F = 4.6, df = 2.10, p < 0.05) and IL-2-
deprivation in 30 healthy adults, showed that in the like activity (F = 2.2, df = 16.58, p < 0.01) [219]. Later
morning after a night of sleep loss, in addition to a sig- studies show that pro-inflammatory biomarker levels in-
nificant increase in monocyte production of IL-6 and cluding C-reactive protein (CRP), IL-6, IL-1β, IL-17 and
TNF-α, more than 3-fold increase in transcription of IL- IFNγ are elevated during experimental sleep deprivation
6 messenger RNA and a 2-fold increase in TNF-α mes- [177, 220–222]. In a study by Vgontzas et al., it has been
senger RNA were detected [48]. A meta-analysis study suggested that 1 week of sleep deprivation can lead to a
written by Irwin M.R. et al. including 72 studies (total significant overall increase in 24-h secretion of IL-6 by 0.8
patients number was > 50,000) suggested the association ± 0.3 pg/ml; p < 0.05 and TNF-α by 0.26 ± 0.1 pg/ml; p <
of sleep disturbance and occurring inflammation. This 0.01. In this study, the impacts of sleep restriction for 7
study suggested that sleep disturbance was associated days in 25 healthy young samples were studied [223]. An-
with higher levels of CRP (ES .12; 95% CI = .05–.19) and other study written by Patel et. al also demonstrated an as-
IL-6 (ES .20; 95% CI = .08–.31) [176]. sociation between habitual sleep duration and levels of
In the next section, we discuss the common inflamma- pro-inflammatory cytokines such as CRP, IL-6, and TNFα
tory components in both AD and insomnia, separately. levels based on the questionnaires completed by 614 indi-
viduals [47]. CRP production in the liver can be stimulated
Inflammatory cytokines and cells by IL-6 so sleep duration has effects on CRP levels sec-
Innate immunity is the first line of defense against ondary [47]. It has been suggested that increased levels of
tissue damage and microbial infection [195]. Mono- the circulating proinflammatory cytokines may be a result
cytes, macrophages, and dendritic cells are the im- of the activation of monocytic populations which are pri-
mune cells of the innate immune system and within mary immune sources of IL-6 and TNF [224].
minutes to hours after detecting a foreign challenge, Experimental studies describe that elevations in circu-
become activated, and initiate a cascade of inflam- lating TNFα levels and TNF-α gene expression occur in
matory processes that activate the key intracellular monocytes following sleep restriction. Irwin et al., by
transcription factors such as NF-κB and activator assessing the monocyte proinflammatory cytokine pro-
protein-1 (AP-1). Activation of NF-κB leads to the duction in 30 healthy adults via DNA microarray ana-
production of proinflammatory cytokines including lyses during the day and after partial sleep deprivation,
TNF and IL-1 that have roles in the inflammatory suggested the impact of sleep loss on the transcription
response [187, 195]. of proinflammatory cytokine genes and as it is men-
A mechanism that has roles in nocturnal increases in tioned above sleep loss induced a 2-fold increase in
proinflammatory cytokines is an accumulation of hazard TNF-α messenger RNA [48]. Also, Vgontzas et al.
signs including reactive oxygen species, nucleotides such showed that sleep deprivation led to a significant in-
as adenosine triphosphate, and heat shock proteins dur- crease in the overall 24-h TNFα secretion (0.26 ± 0.1
ing the wake period which leads to increased production pg/ml; p < 0.01) in 25 young and healthy sleepers [225].
of proinflammatory cytokines and then can support the It has been suggested that in patients with chronic in-
initiation of adaptive immune responses [196]. somnia, chronic alterations in sleep patterns can change
Table 1 Association of the pro-inflammatory cytokine with the AD

Cytokine CNS origin Aβ deposition Neurons Tau protein Reference
IL-1 Astrocytes, Glial cells, Neurons ↑ Death of neurons ↑ Tau [199–203]
Invasion of neutrophils into CNS ↑ phosphorylation ↑
Release of toxins from glial and
endothelial cells↑
IL-6 Microglia, Astrocytes ~ Anti-apoptotic Tau [204–206]
phosphorylation↑
IL-18 Activated microglia, astrocytes, ependymal ↑ Pro-apoptotic Phosphorylation of [207–209]
cells, neurons tau↑
IFN-ɣ T cells, Glia, Neurons ↑ Neural degeneration ↑ phosphorylation of [210–213]
tau↑
TNF-α Microglia, Astrocytes, Neurons ↑ Pro-apoptotic Tau [214–216]
phosphorylation↑
IL-12 Glial cells , Activated blood monocytes Aβ Pro-apoptotic ↑ Tau levels in CSF ↑ [217, 218]
deposition↑
↑: increase
↓: decrease
~: both increase and decrease
the diurnal pattern of cytokine secretion [223, 225, 226]. The hyperexpression of some pro-inflammatory cyto-
In a study written by Vgontzas A.N. et al. in 2002 which kines, including interleukin-1 (IL-1), interleukin-6 (IL-6),
was discussed above, by assessing 11 insomniacs and 11 interleukin-18 (IL-18), TNF-α, interferon (IFN), and
healthy controls, it has been shown that IL-6 and TNF interleukin-12 (IL-12), has been detected in brain and
are fatigue-inducing cytokines so it is hypothesized that CSF in both animal studies and patients [18, 19].
the daytime secretion of IL-6 is negatively influenced by Based on the aforementioned studies, C-reactive
the quantity and quality of the previous night’s sleep protein (CRP), interleukin-6 (IL-6), IL-1β, IL-17, and
[223]. Several studies surprisingly suggest women appear TNF are elevated in insomnia and sleep deprivation
to be especially vulnerable to the effects of sleep loss on and there are studies that suggest that sleep and
cellular inflammation and overproduction of inflamma- wake changes could increase the risk of cognitive de-
tory biomarkers such as IL-6 and CRP [49, 176, 227]. cline [93, 235].
In sleep disorders and insomnia, blood cell count So here are the associations of elevated neuroinflam-
changes can be seen either. For example, there are stud- matory cytokines and chemokine in insomnia with AD
ies that demonstrate the decline in natural killer cell pathogenesis:
(NK) responses. Irwin et al., in a study, demonstrated re- IL-1 can be produced by glial cells and neurons [6]. In
duction of NK cell activity to a level 72% of the mean the AD brain, it accumulates in the hippocampus due to
baseline values (p < 0.01) after sleep deprivation in vol- stress injury and has a significant effect on hippocampal
unteers [228]. Also in another human study, they sug- synaptic function [6, 236]. Based on studies the levels of
gested decreased NK activity, and lower stimulated NK IL-1, in CSF and/or serum of patients who have AD, are
activity, as compared with the controls [229]. In the higher than in healthy controls [199, 237–239]. Blum-
lymphocyte subsets studies, reduction in cell counts in Degen D. et al. showed that IL-1β was significantly ele-
blood during the night and its decrease during subse- vated in the CSF of de novo AD patients in comparison
quent daytime was shown in sleep, in comparison with to the control group [240]. The early overexpression of
continuous wakefulness. This is true for T helper cells, IL-1 in AD is related to the proliferation and subsequent
CTL, activated T cells, and monocytes [42, 230, 231]. loss of dystrophic neuritic elements in Aβ plaques [241],
For more than a decade, studies have indicated that and it clarifies that IL-1 plays a key role in plaque evolu-
the immune system may have a role in AD; however, in- tion and in particular, IL-1 promotes the synthesis and
flammation contributes to and exacerbates AD path- processing of APP. Hence, it may promote further amyl-
ology [232–234]. Neuroinflammation that occurs in AD oid production and deposition in plaques which can lead
is a complex response that can lead to cellular and mo- to AD [199, 200, 242–244]. A correlative relationship
lecular changes, recruitment of peripheral immune cells, also seems to exist; the secreted form of APP activates
induction of some intracellular signaling pathways, and microglia and induces excessive expression of IL-1 [245].
release of inflammatory mediators in the brain. All these IL-1 activates astrocytes [246] and induces their expres-
factors can cause neuronal dysfunction, death, or a com- sion of the secreted acute phase and/or Aβ binding pro-
bination of both in AD [16, 17]. teins [247]. Therefore, it shows that the production of
IL-1 in insomnia and sleep deprivation can make CNS Johansson JU et al. assessed the relationship of CR1
more susceptible to Aβ plaque deposition. genotype, CR1 levels, CR1 structural isoforms, erythro-
IL-6 principally is produced by activated microglia cyte capture of Aβ with AD risk in intravenous blood
and astrocytes in different parts of the brain such as samples from AD subjects [261] and confirmed that sin-
frontal, temporal, parietal, and occipital cortex [248, gle-nucleotide polymorphisms (SNPs) in the CR1 gene
249]. The high levels of IL-6 can be detected in the significantly increases the AD risk.
CSF of AD patients [240]. As is said before, IL-6 Another study written by Afagh A. et al. showed that
levels are elevated in insomnia and sleep deprivation. C1q is localized almost around plaques containing the
Ringheim G.E. et al. showed the enhancement of APP β-pleated conformation of amyloid by assessing the tis-
transcription and expression leading to the IL-6/IL- sue distribution and cell association of C1q in the hu-
6R-complex in an in-vitro study using human fetal man brain with immunocytochemical double-labeling
brain tissues were obtained from 14 to 18 week so it techniques [259].
indicates a prominent role for IL-6 in Alzheimer dis- The significance of the complement activation in AD
order [250]. has roles in the pathological changes in the terminal
Microglia, astrocytes, and neurons have roles in pro- stage of AD and the early alternation in the disease
ducing TNF-α [214]. TNF-α can increase the production course and in vitro studies it has been suggested that Aβ
of amyloid-beta [207, 215] and hyperphosphorylation of can induce complement-mediated toxicity against neu-
tau protein [208]. rons in culture [263, 264, 267–270].
As stated, BACE1 has roles in the production of Aβ The nervous system is susceptible to injury caused by
and accumulation of it, and proinflammatory cytokines complement dysregulation owing to its poorly protected
such as TNFα, IL-1β, and especially IFNγ have been resident cells including neurons and glia [271, 272]. Po-
shown that can increase astrocytic BACE1 expression tential triggers for this dysregulation of complements
and Aβ secretion in cultured human astrocytes and and causing neurodegeneration are legion [258].
astrocytic cell lines [251]. Studies have shown that the complement pathway is
Hence, based on what is said, cytokines and cells activated during wakefulness [273, 274]. Measuring the
which are elevated in insomnia and SD can lead to Aβ immunoglobulins and complement levels in serum can
overproduction and other pathogenesis that occur in help us to assess the function of the immune system and
AD. study the impairment and restorative processes that hap-
pen during wakefulness and sleep and the consequences
Complements due to sleep loss. A study written by Hui L. et al. sug-
Activation of three complement pathways (classical, lec- gests that the immunoglobulins and complement com-
tin, or alternative pathway) has important roles in nor- ponents including IgG, IgA, IgM, C3, and C4 of blood
mal inflammatory responses to injury and can remove samples of healthy volunteers underwent sleep
the invading microbes, apoptotic cells, tissue debris, and deprivation were increased during 24 h and 48 h sleep
aggregated macromolecules. However, inappropriate deprivation which its mechanism was considered to be
complement activation can also lead to injury or death through production and release of the cytokines like IL-
of cells and can be responsible for the disease manifesta- 6. This shows that sleep-wake activity has roles in
tions [252–254]. Complement has been implicated in humeral mediated immunity [275]. Based on the above-
different neurological and neuropsychiatric diseases such mentioned studies, in insomnia and sleep deprivation,
as depression, epilepsy, demyelination, and dementia increased cytokine production leads to activation of the
which complement leads to inflammation and exacer- complement pathway and immunoglobulins secretion
bates the disease [255–258]. thus Aβ increase which is the key role in the pathogen-
One prominent feature of AD neuropathology is the esis of AD.
activation of the classical complement pathway pro-
teins due to the lesions [163]. Aβ and tau-containing Cyclooxygenase enzyme
neurofibrillary tangles directly activate the full range Cyclooxygenase enzyme (COXs) are inflammatory
of classical pathway complement proteins in in vitro agents and enzymes that play roles in the production of
studies [168, 259–265]. For example, Litvinchuk A. the active lipid molecules named eicosanoids, metaboli-
et al. (2018) suggested that the deletion of C3ar1 in zation of the arachidonic acid, and converting them to
mice leads to a decline in tau pathology, attenuation prostaglandins [276, 277]. In addition to a constitutive
of neuroinflammation, synaptic deficits, and neurode- isoform (COX-1), which controls the physiological re-
generation [260]. In another study by Boyett K.W. sponses and is expressed in the most tissues, a second
et al., Clq injections into the hippocampus and cortex and inducible isoform (COX-2) is produced in response
of transgenic mice lead to increased fibrillar Aβ [266]. to injury, growth factors, cytokines, and pro-
inflammatory molecules and is responsible for prosta- hippocampal long-term plasticity (LTP) and leads to res-
noid production in acute and chronic inflammatory con- toration of synaptic function [301].
ditions [278, 279].
Overactivation and overexpression of these enzymes have Blood-brain barrier disruption
putative roles in AD pathobiology as one of the inflamma- The blood-brain barrier (BBB) is a specialized diffu-
tory mechanisms [276, 280–282]. In addition to this inflam- sion barrier and keeps the integrity of the brain by
matory role, it has been shown that they can affect the restricting permeability across the brain endothelium
pathophysiology of the AD via different pathways such as layer and has roles in the normal function of the cen-
localization of the COX enzyme and PGD2 which is a tral nervous system [302]. In fact, BBB is a physical
major metabolic product of COX-2 in the specific cells of barrier via tight junctions between cells, transport
the brain including neurons, microglia cells, and astrocytes, barrier via transport mechanisms that can regulate
specific produced lipids, the interaction of the COXs with the solute flux, and metabolic barrier with the roles
intracellular components that are related to AD-like of metabolizing enzymes [302].
gamma-secretase complex and disruption of hippocampal The barrier’s function is changeable. It can react to
synaptic function and finally leading to cognitive deficits the local changes and requirements and can be mod-
[276, 283–289]. So it has been demonstrated that COX-2 ulated by mechanisms and cells in both physiological
has roles in the cascade of events that cause neurodegener- and pathological conditions [302]. This regulation that
ation in AD. Indeed, studies show elevation of that COX-2 occurs in physiological and pathological circumstances
expression in the AD brain especially in the frontal cortex can be done by changes in tight junction function
and the hippocampal formation leads to clinical dementia [303] and expression and activity of transporters and
[281, 290, 291]. In contrast to PGD2, PGE2 has roles in enzymes [302, 304].
synaptic plasticity, memory, and neuronal protection so it In the normal brain, cerebral endothelial cells control
has a protective role [292, 293]. In Alzheimer’s disease, and restrict the entry of leukocytes and circulating
COX-1 is expressed in microglial cells near the Aβ deposits agents into the brain. In pathologic conditions, released
[279] and COX-2 accumulates in neurons [279, 281, 290]. chemical mediators such as glutamate, aspartate, ATP,
COX-2 expression in neurons can be induced by Aβ, glu- endothelin-1, ATP, NO, MIP-2, TNF-a, IL-β1, bradyki-
tamate, and inflammatory cytokines. It has been shown that nin, histamine, thrombin, substance P, platelet-activating
PGD2 levels are increased in AD [290, 294–296]. It appears factor, and free radicals can increase BBB permeability
that COX-2 expression in the neurons of the hippocampal [305–308]. Some of these molecules are released by
formation occurs in early AD before even neurodegenera- endothelium itself and some are released by terminals of
tion may happen [281]. Immunocytochemical evidence sug- neurons that are close to blood vessels such as hista-
gests that the overproduction of COX-2 in the neurons of mine, substance P, and glutamate, and affect BBB
the hippocampal formation correlates with neuronal atro- permeability.
phy [291]. The COX-2 protein content is increased in neu- A perfect functioning neurovascular unit and BBB are
rons with neurofibrillary tangles and in damaged axons essential for homeostasis and the proper function of
[297] and prior to overproduction of the cytokines such as neurons [309].
IL-6 and TGF-β1 [298]. Change in microvascular permeability and the BBB
Also, in vitro studies show that overproduction of impairment is involved in AD pathology. In several stud-
COX-2 in the AD brain may be the result of exposure of ies, this changed permeability has been detected in the
the neurons to Aβ, which may contribute to Aβ neuro- brains of AD patients and it has been considered to be
toxicity [290] so the relation of COX-2 and Aβ may play one of the notable events of AD [310–313]. A meta-
a key role in mediating the development and progression analysis study by Farrall A.J. based on 31 BBB permeabil-
of AD. ity studies (1953 individuals) of normal aging or with
As it is said above, it has been found that prolonged cerebral microvascular disease suggested that AD pa-
continuous wakefulness and insomnia can lead to im- tients had a greater increase in BBB permeability in
pairments in hippocampal long-term synaptic plasticity comparison to a neurologically healthy control group
and hippocampus-dependent memory formation [299]. (26 comparisons, C:S = 510:547, S.M.D. 0.81, 99% CI
It appears that SD and insomnia lead to overproduction 0.37, 1.26, p < 0.01) [314]. Breakdown in the BBB in AD
of COX-2 then increasing in PGD2 and decreasing in also has been approved by post-mortem brain tissue
PGE2. This suggests that these lipid molecules partici- studies [315–317]. Bowman G.L. et al. has analyzed the
pate in memory consolidation during REM sleep [300]. relationships between biochemical markers of BBB in-
For mentioning the effects of these events on neurons tegrity, clinical risk factors, CNS IgG synthesis, apolipo-
and synapse plasticity, a study shows blocking COX-2 by protein E (APOE) genotype, MR-derived white matter
synthetic and soluble Aβ prevents the inhibition of hyperintensities (WMH), and volume changes via
clinical assessments, brain imaging, CSF and plasma col- It is shown that as a result of the systemic inflamma-
lection, and assessing the CSF–albumin index (CSF-AI) tion and inflammatory mediators overproduction such
for determining BBB integrity over one year in patients as TFN-α, IL-1β, IL-6, CRP, and COX-2, due to insom-
with mild to moderate AD to discover the BBB stability nia and sleep loss, we can detect changes in cellular
and its functional importance [318]. After a year, BBB components of the blood-brain barrier, particularly on
disruption was present in an important subgroup of pa- brain endothelial cells and they can alter the blood-brain
tients with AD (n = 8/36, 22%) at all-time points barrier permeability [332–337].
measured. So based on this information, we can suggest that
In AD, the capillary endothelium degeneration, de- sleep deprivation and insomnia can lead to AD due to
creased endothelial TJ protein levels, the capillary base- the BBB disruption.
ment membrane thickening, and degenerating small
cerebral arteries can lead to impaired BBB function and The neurotrophins
cerebral blood flow impairment [319–323]. As it is said The neurotrophins (NTs) are essential secreted proteins
above, chemicals such as TNF-a, IL-β1 which can be that bind to specific cell membrane receptors to start
overexpressed in AD can influence BBB permeability. signaling pathways and control processes and have mul-
In neurologic conditions including multiple sclerosis tiple functions. They have a widespread expression in
and AD, the integrity of the BBB can be altered due to the CNS and PNS in both developing and adult brain
the migration of leukocytes into the brain [324, 325]. [338, 339]. Their functions are neuronal differentiation
Leukocyte migration into the brain can cause loss of TJ and survival, modulation of neuronal function, axon
molecules including occludin and zonula occludens, pathfinding, and synaptic plasticity. NTs can protect the
stimulation of signal transduction cascades, and finally neurons in conditions such as excitotoxic, hypoxic, and
BBB disruption [326]. hypoglycemic insults [339–347]. NTs have either an in-
The BBB disruption and disturbances can lead patients structive or permissive role in the modification of synap-
to AD either. Skoog I. et al. investigated BBB function in ses which is activity-dependent. In the instructive role,
relation to AD in elderly by the assessment of CSF/ NTs directly change presynaptic transmitter release,
serum albumin ratio as a measure of BBB function. They postsynaptic sensitivity, or synaptic morphology, thus
reported that in 85-year-old AD patients, CSF/serum al- this can lead to a persistent synaptic modification. For
bumin ratios are higher, and the indications of disturbed the permissive role, this modification is developed by
BBB function were started even before the onset of the other associated factors with neuronal activity, although
disease [327]. The positive relationship between CSF- NTs accomplish functions that are essential for the syn-
serum albumin ratio and progression of the disease over apse modification [338].
1 year in AD patients also determines that BBB impair- Nerve growth factors including TGF-β, insulin-like
ment could affect this progress [318]. The dysfunction of growth factor (IGF), epidermal growth factor (EGF),
the BBB may help substances penetrating through the fibroblast growth factor (FGF), interleukin-6, bone mor-
BBB more rapidly to interact with neurons, and lead to phogenetic protein (BMP), and platelet-derived growth
events include involving amyloid accumulation and Alz- factor (PDGF) were the first members of the neurotro-
heimer encephalopathy [323]. So we can understand that phin family that were found in the early 1950s as pro-
the BBB disruption and AD have a bilateral relationship. teins that have roles in sympathetic and sensory neurons
Sleep is a homeostatic process. Sleep disruption and survival and growth during development [339, 348, 349].
insomnia may have negative consequences depending on Among these neurotrophic factors, NT is prominence
an acute or chronic course. Many studies of experimen- because of its roles and distribution in the nervous sys-
tal sleep impairments also suggest that sleep loss tem. In mammals, this family has four structurally re-
influences neural functions and cerebral blood flow lated neurotrophins: NGF, brain-derived neurotrophic
[328–330]. An animal study written by He J. et al. shows factor (BDNF), neurotrophin-3 (NT-3), and
that chronic sleep impairment affects neuroendocrine neurotrophin-4 (NT-4, which also known as NT-4/5)
regulation and changes BBB structure and function dir- [350]. After the NGF discovery as the prototypic NT,
ectly in mice. They determined how sleep restriction can Barde et al. isolated a neuron survival factor from pig
change the permeability of the BBB based on the brain brain, which was named brain-derived neurotrophic fac-
uptake of sodium fluorescein. After injecting sodium tor (BDNF) that is homologous in protein sequence to
fluorescein, in the control group, BBB had the lowest NGF [351]. BDNF is an NT which has a widespread ex-
permeability in the cerebral cortex and it was higher in pression in the developing and adult mammalian brain
the brainstem and cerebellum but in the sleep restriction and has been suggested by several studies that have ef-
model, the sodium fluorescein uptake was increased in fects on synaptic plasticity and is related to various
the cerebral cortex [331]. physiological functions in the brain especially relevant in
neuroplasticity, memory and sleep [339, 352, 353]. For As is said above, neurodegeneration of the basal
example, it was elucidated that BDNF has a crucial role forebrain cholinergic which are the main source of
in activity-dependent long-term synaptic plasticity by acetylcholine to the cortex and hippocampus can re-
the impairment of hippocampal long-term potentiation sult in AD and they become atrophic in the disease
(LTP) in BDNF knock-out mice [354, 355]. Also, Lohof [383, 384]. These neurons have roles in higher CNS
et al. showed that applying exogenously BDNF enhances functions such as learning, memory, and attention
synaptic efficacy at neuromuscular junctions in culture [385, 386]. The loss of cognitive function due to AD
[356]. Soon thereafter, BDNF, other types of NTs such has been attributed to the degeneration of this trans-
as NT-3 and NT-4/5 were suggested to promote gluta- mitter system [387]. As a consequence of a life-long
matergic synaptic transmission in the hippocampus of dependence of basal forebrain cholinergic neurons on
the mammalian CNS [357–359]. the retrograde supply of the NTs for their cholinergic
In AD, neurotrophic factors play a protective role in phenotype [388], the relation of NTs to AD has been
the survival of neurons that are affected by degenerative mentioned.
processes [343, 360]. So changes in the neurotrophic fac- Sleep has an important effect on cognitive functioning
tors and their receptors regulation can cause neurode- such as the consolidation of synaptic plasticity and long-
generation and they are observed in both AD animal term memory. Another disorder that has been shown its
models and patients [361, 362]. Neurotrophic factors relation to BDNF and other NTs is sleep deprivation
prohibit cell death, cause the neuronal proliferation and and insomnia. The impact of sleep deprivation on cor-
maturation, and have roles in the improvement of tical and hippocampal BDNF expression and serum
growth and function of affected neurons in AD [344, BDNF levels has been elucidated in both animal models
363, 364]. In this context, the neurotrophin BDNF is and patients [389–392]. Serotonin is the main neuro-
highlighted. transmitter which is responsible for the regulation of
Reduction by half in BDNF mRNA, its precursor both sleep-wake circadian cycles and mood states con-
(proBDNF), and mature BDNF concentration have trolling [393]. It is shown that BDNF production is stim-
been detected in the entorhinal, frontal, temporal, and ulated by serotonin and BDNF improves serotonergic
parietal cortex, hippocampus, and basal forebrain of signaling [394, 395]. It has been demonstrated that pa-
AD brains and in mouse models of amyloid pathology tients with symptoms of insomnia showed notably de-
[365–373]. Although, because the main source of creased serum BDNF levels in comparison with healthy
serum BDNF is cortical, it seems that serum levels of controls which this reduction significantly was related to
BDNF relatively shows its CNS expression levels the severity of insomnia [396, 397]. However, in addition
[374]. By measuring the serum BDNF, it has been to reduced BDNF levels due to insomnia, wakefulness
suggested that its reduction happens early in AD pro- gave during SD, as an acute stressor for the brain, cause
gression, prior to plaque deposition in transgenic ani- an increase in BDNF content [398, 399]. Therefore,
mals [372] and relates to the degree of cognitive chronic stress leads in long-term sleep disturbance and
impairment in humans [368]. BDNF is an important decrease of BDNF levels while acute stress elevates
regulator of learning and memory processes which is BDNF levels which became clear in attention to that the
particularly abundant in the prefrontal cortex [342, acute stress induces glutamate transmission increase
375], and reduced BDNF signaling through TrkB which is related to corticosterone receptors activation,
leads to impaired spatial memory [376, 377]. Mature whereas chronic stress leads to opposite results.
BDNF enhances synapses, though proBDNF weakens Therefore, sleep deprivation can lead to BDNF reduc-
synapses. This information shows the importance of tion and based on the roles of BDNF and its effects on
the ratio of proBDNF to BDNF in synaptic plasticity memory and synapses it can be suggested that through
[378, 379]. Preclinical reports suggest a decrease in this impairment and reduction, SD and insomnia can re-
cortical BDNF expression in AD models and BDNF- sult in AD and dementia.
mediated TrkB retrograde transport impairment in
neuronal culture can lead to β-amyloid peptides. Also, Aging and cognitive function
β-amyloid overproduction can decrease the signaling As it is mentioned, dementia is a common disease
of BDNF in cortical neurons [373, 380] and can dir- among the elderly [1, 400, 401] but just preclinical im-
ectly inhibit the proteolytic conversion of BDNF from pairments may be expected decades before certain diag-
pro-BDNF and cause reducing its levels and by dis- nosis and cognitive decline may not be seen until
rupting its axonal transport can modify BDNF levels discussed mechanisms including the accumulation of
at the synapses [381]. It has been demonstrated that amyloid and NFT, inflammatory processes, BBB disrup-
the binding of BNDF to TrkB can control the pro- tion, loss of synapses, and neuron loss have reached a
duction of APP in vitro [382]. certain threshold [11, 402–406].
Same as AD, insomnia and SD also are more prevalent essential mechanisms to the pathogenesis of AD [51,
in older adults [407–411]. It has been suggested that 56]. Also, sleep impairment can lead to:
chronic sleep impairment has effects on cognitive func-
tion in the elderly [410, 412–414]and it is considered as 1. Induction of the extracellular release of tau [129,
a risk factor for the initiation and progression of AD in 159] which this increase can result in
them [88, 415, 416]. Cricco et al. [417], in a longitudinal neurodegeneration and neuron loss and can explain
study of 6444 men and women (age 65 and older) with the association of insomnia to AD pathogenesis [53,
chronic symptoms of insomnia who were cognitively in- 95, 160, 161].
tact at baseline, showed that men with chronic insomnia 2. Inflammation through increasing levels of
had an increased risk of cognitive decline independent proinflammatory cytokines and inflammatory agents
of depression than those free of insomnia (49% more and enzymes such as IL-6, TNF-α, and IL-1, and
likely) and for women with chronic insomnia, an in- CRP and COX levels. However, the differences in
creased risk of cognitive decline was detected, but only the characterization of sleep disturbance, different
in those who had severe depressive symptoms. In an- assessment ways used to evaluate sleep disturbance
other study by Cross et al. [418], after assessing the asso- such as sleep quality or other sleep complaints like
ciation between insomnia disorder and cognitive sleep duration, and various markers of inflammation
function among middle-aged and older adults (> 45 years have led to not establishing confident results about
old) by self-report questionnaires, it has been suggested the relation between sleep disturbances and
that insomnia disorder in older adults is more associated inflammation.
with impaired memory than adults with insomnia symp- 3. The BBB disruption [334, 335] and 4. Declining in
toms alone or without any sleep complaints. Also, Hai- the neurotrophins levels which are essential
mov et al. [419] explored the association between proteins for neuron survival, modulation of
chronic insomnia and changes in cognitive functioning neuronal function, and synaptic plasticity and have
among older adults (64 older adults without insomnia roles in neuroplasticity, memory, and sleep [339,
and 35 older adult insomniacs). They found that older 352, 353]. Based on mentioned papers, these
adult insomniacs displayed impaired performance espe- conditions due to insomnia can provide a basis for
cially in memory compared to older adult good sleepers. being affected by AD.
Therefore, based on the related mechanisms that can
lead insomnia to the development of AD, and with at- In addition to declared events that link these two dis-
tention to the high prevalence of insomnia and sleep disorders, it is important to mention that both insomnia
orders among the elderly age group, it can be assumed and AD are more prevalent in the elderly [1, 400, 401,
that insomnia has possible effects on AD pathogenesis 407, 408]. The pathogenesis of AD begins years earlier
and cognitive deficit in older adults with Alzheimer’s before the cognitive decline occurrence [11, 402–406].
disease risk. So based on the impacts of insomnia on AD develop-
ment, chronic sleep disorders in the elderly can deterior-
Discussion ate cognitive function in them [410, 412–414], and [417]
This review highlights mechanisms by which chronic can exacerbate the symptoms of AD [88, 415, 416].
sleep deprivation and insomnia disorder may result in Based on these similarities between the pathophysi-
AD risk. AD is a common progressive neurodegenerative ology of insomnia and mechanisms that cause AD in-
disease characterized by the accumulation of β-amyloid cluding accumulation of Aβ, inflammation, and other
(Aβ) peptides and hyperphosphorylated tau proteins and components which are discussed in this review, insom-
starts by Aβ and tau deposition [6, 10, 11]. Neuroinflam- nia disorder can be linked to AD risk [420–422] and this
mation is another main part of AD pathogenesis which could be a novel target for treatments or prevention AD
occurs by the leukocytes and T cells, glial cell activation, development and/or resolve the cognitive decline in pa-
and inflammatory mediators release such as IL-1, IL-6, tients with AD in the future [423].
IL-12, IL-18, TNF-α, and IFN. These molecules are over-
produced during the disease and can cause neuronal Conclusion
dysfunction or death [13, 16–19]. Regarding to possible This study provides information suggesting SD and in-
correlation between insomnia and AD, we reviewed the somnia possible effect on memory impairments and AD
common mechanisms in both AD and chronic insomnia. neuropathogenesis and development by exacerbating im-
Aβ is considered as the major pathological agent of portant biochemical processes. Therefore, the correction
AD. It is demonstrated that insomnia can lead to an in- of sleep disorders including insomnia and sleep
crease in the levels of Aβ of CSF and this Aβ can cause deprivation could be a potential therapeutic strategy for
synaptic dysfunction and neurotransmission impair, individuals with AD risk.
Abbreviations 7. Dubois B, et al. Advancing research diagnostic criteria for Alzheimer's

AD: Alzheimer’s disease; Ap-1: Activator protein 1; APOE: Apolipoprotein E; disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6):614–29.
APP: Amyloid precursor protein; Aβ: Amyloid-beta; BACE-1: β-site APP 8. Mormino EC, et al. Synergistic effect of β-amyloid and neurodegeneration
cleaving enzyme I; BBB: Blood-brain barrier; BDNF: Brain-derived neurotrophic on cognitive decline in clinically normal individuals. JAMA Neurol. 2014;
factor; BMP: Bone morphogenetic protein; CNS: Central nervous system; 71(11):1379–85.
COX: Cyclooxygenase enzyme; CRP: C-reactive protein; CSF: Cerebrospinal 9. Wagner M, et al. Biomarker validation of a cued recall memory deficit in
fluid; DLB: Dementia with Lewy bodies; EGF: Epidermal growth factor; prodromal Alzheimer disease. Neurology. 2012;78(6):379–86.
ER: Endoplasmic reticulum; FGF: Fibroblast growth factor; 10. Chen H-H, et al. Changes in tau protein landscape during Alzheimer's
FTLD: Frontotemporal lobar degeneration; GSK-3: Glycogen synthase kinase; disease Progression. Alzheimer's Dement. 2017;13(7):P1296.
IFN: Interferons; IGF: Insulin-like growth factor; IL: Interleukin; ISF: Interstitial 11. Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology
fluid; LTP: Long-term plasticity; LTP: Long-term potentiation; of Alzheimer's disease. Trends Pharmacol Sci. 1991;12:383–8.
NF: Neurotrophin; NFT: Neurofibrillary tangle; NF-κB: Nuclear factor-kB; 12. Šimić G, et al. Tau protein hyperphosphorylation and aggregation in
NK: Natural killer cell; NREM: Non-rapid eye movement; PD: Parkinson’s Alzheimer’s disease and other tauopathies, and possible neuroprotective
disease; PDGF: Platelet-derived growth factor; REM: Rapid eye movement; strategies. Biomolecules. 2016;6(1):6.
SD: Sleep deprivation; SR: Sleep restriction; SNP: Single-nucleotide 13. Minter, M.R., J.M. Taylor, and P.J. Crack, The contribution of
polymorphism; TNF: Tumor necrosis factor; WHO: World Health Organization; neuroinflammation to amyloid toxicity in Alzheimer's disease. 2016. 136(3):
WMH: White matter hyperintensities p. 457-474.
14. Popp J, et al. Markers of neuroinflammation associated with Alzheimer's
Acknowledgments disease pathology in older adults. Brain Behav Immun. 2017;62:203–11.
Tehran University of Medical Sciences supported this study. 15. Chen JH, et al. Protection of TGF-beta1 against neuroinflammation and
neurodegeneration in Abeta1-42-induced Alzheimer's disease model rats.
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The Effect of Insomnia On Development of Alzheimer 'S Disease

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Sadeghmousavi et al.

Journal of Neuroinflammation (2020) 17:289

REVIEW Open Access

The effect of insomnia on development of

Introduction AD is a progressive neurodegenerative disorder char-

Table 1 Association of the pro-inflammatory cytokine with the AD

Abbreviations 7. Dubois B, et al. Advancing research diagnostic criteria for Alzheimer's

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