Circadian dysfunction and Alzheimer's disease – An updated review

Abstract Alzheimer's disease (AD) is considered to be the most typical form of dementia that provokes irreversible cognitive impairment. Along with cognitive impairment, circadian rhythm dysfunction is a fundamental factor in aggravating AD. A link among circadian rhythms, sleep, and AD has been well‐documented. The etiopathogenesis of circadian system disruptions and AD serves some general characteristics that also open up the possibility of viewing them as a mutually reliant path. In this review, we have focused on different factors that are related to circadian rhythm dysfunction. The various pathogenic factors, such as amyloid‐beta, neurofibrillary tangles, oxidative stress, neuroinflammation, and circadian rhythm dysfunction may all contribute to AD. In this review, we also tried to focus on melatonin which is produced from the pineal gland and can be used to treat circadian dysfunction in AD. Aside from amyloid beta, tau pathology may have a notable influence on sleep. Conclusively, the center of this review is primarily based on the principal mechanistic complexities associated with circadian rhythm disruption, sleep deprivation, and AD, and it also emphasizes the potential therapeutic strategies to treat and prevent the progression of AD.

symptoms are present for several patients with AD even before the final medical diagnosis of AD. Based on multiple studies, it is seen that sleep disturbances can lead to neurodegeneration and even cognitive impairment. In the future, it can be utilized as a biomarker for neurodegeneration. In one study, it is seen that older women with diminished and irregular circadian rhythms have a higher risk of developing one of the types of impairments of AD, such as mild cognitive impairment and dementia. Various studies suggest that 25%-66% of patients with AD face sleep disruption, which can be easily noticeable. [11][12][13][14][15][16][17] Melatonin (N-acetyl 5-methoxytryptamine) is a hormone regulated by the circadian rhythms, and it plays a vital role in the neurodegenerative event of AD. 18 The primary source of melatonin is the brain's pineal gland, but other organs like the retina, bone marrow, kidney, pancreas, skin, and glial cells are also involved. Melatonin is a multifunctional hormone that regulates circadian rhythm and shows anti-inflammatory, cytoprotective, and anti-oxidant properties. The circadian clock regulates melatonin and during a study in rat and mice models, melatonin shows the highest plasma melatonin level at midnight. 19,20 Melatonin production decreases with aging which can be considered a critical factor for the onset of AD. When impairment or disruption is seen in the suprachiasmatic nucleus (SCN), melatonin levels are reduced, resulting in circadian rhythm disruption. [21][22][23] Even reduction in CSF is linked with melatonin, and, finally, melatonin progresses AD by causing oxidative damage in the AD brain. Patients with AD have a low level of melatonin as compared with healthy patients. Melatonin can be a promising therapeutic approach to inhibit AD progression as it has free radical scavenging properties as well as anti-amyloidogenic properties. Melatonin also inhibits the secretion process of soluble amyloid precursor protein (APP) in various cell lines through APP maturation. Melatonin administration attenuates amyloid beta generation and deposition in vitro and in vivo models. [24][25][26][27][28][29][30][31][32][33][34] A sundowning phenomenon enhances mental health decline, confusion, and agitation in patients with AD, whereas melatonin reduces the symptoms of sundowning and enhances cognition. In this review, we discuss the association of circadian dysfunction with AD pathology as well as a few pharmacological and non-pharmacological interventions for sleep disruption in patients with AD. 35 (CRY1 and 2), and Reverb (NR1D1 and NR1D2) genes are negative F I G U R E 1 Twenty-four hour biological clock in the human brain and its circadian disruption feedback regulators which suppress the positive limb. The SCN helps in the synchronization of cellular oscillators across organs in humans.
The retina sends light and dark signals to the SCN, which further regulates it. It synchronizes the core clock oscillations in neurons, ultimately translated into oscillatory synaptic output, which transfers the signals to the multiple nuclei in the hypothalamus. All these patterns in neuronal activity, and behavioral and physiological arrhythmicity can be lost post ablation of the SCN. [40][41][42][43][44][45] The circadian clock system is shown in Figure 1, and relationship between circadian rhythm and AD is shown in Figures 2 and 3.

| CHOLINERG IC DIS TURBAN CE S AND CIRC AD IAN DYS FUN C TI ON IN AD PATHOLOGY
Neurodegeneration can also be seen in the basal cholinergic forebrain. Disruption in circadian rhythm can also occur due to cells of the nucleus basalis magnocellularis, which projects to the SCN.
Enrhardth reported that in rats, there are increased phase delays in response to lights when the cholinergic basal forebrain projects to the SCN. This study suggests a relationship between AD neurodegeneration and the circadian clock's signal entrainment ability. [46][47][48]

| NEURONAL LOSS IN THE SCN AND CIRC AD IAN DYS FUN C TI ON IN AD
During the autopsy of patients with AD, it was seen that there is a neuronal loss in the SCN, which is related to loss of amplitude in the circadian rest-activity pattern. Apart from MT1, melatonin receptor expression was disturbed, which resulted in the SCN responding to the phase resetting signal and generating daily rhythms. 49,50

| CIRC AD IAN G ENE DELE TI ON AND CIRC AD IAN DYS FUN C TI ON IN AD
Deletion mutations in the circadian clock gene cause neuronal injury.
Core circadian clock disruption is directly linked to neurodegeneration in AD. BMAL1 is considered to be one of the core genes of the master clock, and a study conducted in mice has shown the deletion F I G U R E 2 Crosstalk between sleep deprivation and Alzheimer's disease. Aβ, amyloid beta of BMAL1 in the hippocampus and cortex. In mice, we observe normal behavioral rhythms and normal sleep wake cycles assessed by wheel running actigraphy and electroencephalogram, respectively, in the presence of severe cortical astrogliosis, synaptic degeneration, and oxidative brain region damage in specific BMAL1 knockout mice. These mice are closely related to transcription multiple redox defenses linked with circadian impairment. Low levels of BMAL1 in the brain also lead to neurodegeneration caused by mitochondrial toxin B nitropropionic acid. The data suggest that decreased BMAL mediated transcriptional exacerbate neurodegeneration in AD.
Clock-gene regulation and better insight into the linkage of clock genes and neurodegeneration require further research and a deeper understanding to examine such regulations. [56][57][58][59] The effect of different clock genes on animal models is shown in Table 1.

| MI CROG LIA , A S TRO C Y TE , AND CIRC AD IAN DYS FUN C TI ON IN AD
Activation of microglia and astrocyte leads to neuroinflammation, which ultimately causes neurodegeneration. Astrocyte activation can be observed to model clock gene deletion in the in vitro model. Even the inflammatory response of microglia leads to variation in the functional circadian clock. Rev-Erb alpha regulates pro-inflammatory cytokine production in macrophages. Finally, inflammation shows the effect of the circadian clock as both Rev-Erb alpha suppressing BMAL1 levels in macrophages in response to lipopolysaccharides. Therefore, the BMAL1 expression in the surrounding glia and neurons can be suppressed by cortex inflammation causing impairment of BMAL1-associated genes, ultimately leading to neurodegeneration. 56,60

| OXIDATIVE S TRE SS AND CIRC AD IAN DYS FUN C TI ON IN AD PATHOLOGY
Numerous studies support the presence of augmented oxidative stress in AD. Less concentration of glutathione and catalase with higher consumption of oxygen (20%-30%) and a higher amount of polyunsaturated fatty acids make the brain a highly vulnerable target for lipid peroxidation. [61][62][63] Lipids peroxidation interrupts cellular functions, followed by neuronal membrane destruction, and the production of highly reactive electrophilic aldehydes, including acrolein, malondialdehyde, and 4 hydroxy 2-nomial (elevated in AD brains). [64][65][66] Oxidative stress also damages nucleic acid and proteins. The role of oxidative stress etiology in AD pathogenesis is still unknown. In 1985, the activity of antioxidants, like superoxide dismutase and glutathione peroxidase with oxidative damage in the day-night cycle in the rat cerebral cortex, whereas in humans, anti-oxidants and circadian rhythmicity protect cells from oxidative damage. [67][68][69][70] The levels of glutathione reductase, glutathione peroxidase, superoxide dismutase, catalase, uric acid, and peroxiredoxin are high in the morning. In contrast, ascorbic melatonin and plasma level are high in the evening or night. This proves that oxidative stress leads to oxidative damage with the progression of AD, which is ultimately regulated by circadian dysregulation. 71

| ERK /MARK AND CIRC AD IAN DYS FUN C TI ON IN AD
Cognitive impairment is the first symptom observed in AD. Impairment, such as memory, is enhanced by short-term stress and F I G U R E 3 Linkage between circadian rhythm and Alzheimer's disease. Aβ, amyloid beta; EEG, electroencephalogram; nREM, non-rapid eye movement; SCN, suprachiasmatic nucleus impaired by long-term stress, and the number of dendritic synapses decreases due to high cortisol levels during chronic stress. 72 The pathway primarily revolves around memory consolidation, and the level of phosphor-ERK CAMP, phosphor CREB, and activity of PKA and MEK are associated with a circadian rhythm.
Moreover, the SCN regulates the hippocampus' Camp/PKA/ERK/ CREB signaling pathway. [73][74][75] The CREB/ERK/PKA/CAMP signaling pathway increases during rapid eye movement sleep. They are even ablating the BMAL1 gene results in reduced Per1 and PERK levels. A study reported that ERK appears overactivated and memory is improved by pharmacological inhibition of ERK in an AD mouse model, whereas memory impairment is seen due to reduction of pCREB level downstream of the ERK pathway. 76  APP-PS1 mouse model Casein kinase 1 isoforms ε and δ with inhibitor PF-670462 reduce amyloid and plaque size as well reduce Aβ signal in the prefrontal cortex and hippocampus, which proves chronotherapy as a promising tool to improve behavior in mice 103 2. Two-month-old female APPSwe/PS1dE9 mice Female APPSwe/PS1dE9 mice show abnormal locomotor activity in which clock gene expression of clock genes Per 1, Per 2, Cry 1, and Cry 2 was increased during night time compared to day type in wild type control mice as Cry 1 and Cry2 expression was low in APPSwe /PS1dE9 mice. This study proves APPSwe /PS1dE9 mice as a most promising AD model to test therapeutic agents related to behavioral and circadian rhythm changes. 104

Cultured fibroblasts and brain samples
BMAL1 is a positive regulator of the circadian clock, and in cultured fibroblasts, DNA methylation regulates BMAL1 rhythms which is linked to circadian alteration in AD 105

4.
Tg 4510 mice In Tg4510 mice, it is seen that there is tauopathy in SCN and even disruption in PER2 and BMAL1 in the hypothalamus of Tg4510 mice. This study proves that tauopathy can lead to normal circadian clock function disruption. 106

AD brain
In this study, the glial fibrillary acid protein in human astrocytes is suppressed as there is an elevation in CLOCK and BMAL, which cause functional impairment by inhibition of aerobic glycolysis in AD 107 6. 5XFAD mouse model Rev-erbα, a circadian repressor, decreases amyloid plaque number and size in the 5XFAD AD mouse model. Even Rev-erbα show a neuroinflammatory effect, which proves Rev-erbα as a novel therapeutic target.
approved system has been developed to evaluate the functionality of the glymphatic system in humans. Recently, the glymphatic system has even played a role in glaucoma pathogenesis, characterized by progressive degeneration of RGCs and amyloid beta accumulation. This activity is higher during sleep and low during wakefulness.

| ME TABOLIC CHANG E S AND CIRC AD IAN DYS FUN C TI ON IN AD
Circadian/sleep disruption may be mediated by metabolic changes in neurodegenerative disorders, particularly AD. Insulin resistance has been linked to an increased risk of AD in clinical studies, and childhood obesity can also cause cognitive impairment later in life apart from diabetes. Apolipoprotein E (APOE) is a key regulator of lipid metabolism found primarily in brain astrocytes. The APOE 4 allele can cause mitochondrial dysfunction, leading to insulin resistance and metabolic defects as a major risk factor for AD. [93][94][95][96][97][98] A recent study suggests that peripheral metabolic dysfunction plays a role in the development of AD-related neuropathology. The clock regulates the majority of metabolic activity, and the loss of circadian clocks has been linked to cellular and system-wide metabolic deficits. Sleep deprivation significantly impacts metabolism, including an increase in insulin resistance markers. Based on these findings, it is enticing to believe that sleep disruption increases the risk of AD by disrupting metabolism. 99-102

| MEL ATONIN A S A PROMIS ING THER APEUTI C TARG E T FOR AD
In AD, melatonin has shown multiple beneficial effects, like prevention of mitochondrial dysfunction, inhibition of amyloid beta toxicity, free radical scavenging, and even circadian dysregulation like sundowning and sleep disturbances. 110 Melatonin even has blood-brain barrier crossing capacity, anti-oxidant properties, as well as balanced amphiphilicity. Amyloid beta peptides are mainly produced with the help of amyloidogenic beta-amyloid precursor protein (beta APP). , and Bcl2 associated BAX, reducing neuronal death. [116][117][118][119][120][121] Melatonin has an anti-oxidant property that reduces oxidative stress.
In an experimental study, it was observed that NF-KB commenced IL-6 in amyloid beta treated brain slices can be inhibited by melatonin in a concentration-dependent fashion. Melatonin injection (ie, 5 mg/ kg, 0.1 to 10 mg/kg, and 10 mg/kg) in the rat in which melatonin shows anti-inflammatory effects and reduces neuroinflammation by increasing ATP production, stimulating GPX activities, and even enhances SOD activity. 122 Therefore, this evidence shows the antineuroinflammatory effects of melatonin on AD. RevErb is a small molecule agonist of the nuclear receptor that can improve metabolic function in mice by directly affecting circadian rhythms. Finally, the right targeting of the circadian clock could be a promising remedial option for treating AD. 33

FU N D I N G I N FO R M ATI O N
No funding was received for this study.

CO N FLI C T O F I NTE R E S T
The authors declare they have no conflict of interest.