Attention has been paid to the possible association between amyloid-beta (Aβ) protein and sleep in AD patients. Aβ level and tau level in cerebrospinal fluid correlates with the Alzheimer's disease onset [7
]. Ju et al. studied the relationship between the quality of sleep as measured by actigraphy and Aβ42 concentration in cerebrospinal fluid in 145 patients aged 45 years or more with normal cognitive function; they reported that Aβ deposition was detected in 22.5% of all patients and those with Aβ deposition had significantly lower sleep efficiency than those without Aβ deposition [9
]. The relationship between CRSD and Aβ has also been studied in animal models. In 3xTg-AD mice, a mouse model of AD engineered to express amyloid precursor protein (APP) with mutations in the presenilin 1(Psen1)gene and to express tau protein, circadian rhythm disorder is observed even before the appearance of brain Aβ protein and neurofibrillary tangles [10
]. In APPswe/PS1σE9 mice, another mouse model of AD showing abnormal Aβ production due to APP expression and Psen1 gene mutations, the sleep/wake rhythm cycle, which was normal in the absence of Aβ plaque formation, was severely disturbed after Aβ plaque formation [11
]. It has also been suggested that the REM sleep deprivation is associated with tau accumulation [12
]. Thus, the relationship between Aβ accumulation and the development and progression of sleep disorder
is suggested to be mutually.
The suprachiasmatic nucleus (SCN) is an important brain region associated with CRSD. The SCN is a known circadian pacemaker in mammals, including humans. Stephan and Zucker have demonstrated that the focal destruction of the SCN results in the loss of circadian rhythm [13
]. The number of cells in the SCN decreases with increasing age, which is particularly evident in the elderly. Moreover, this decreased cell number in the SCN is more profound in AD patients than in normal elderly subjects [14
]. About half of the cells in the SCN express arginine-vasopressin (AVP) and also its receptors, V1a and V1b, indicating that an inter-cellular local neural network is formed in the SCN that controls the circadian rhythm [15
]. AVP mRNA expression is significantly decreased in AD patients, down to one-third of that in normal elderly [16
]. Studies have also shown that the periodic change in the gene expression of vasoactive intestinal peptide (VIP) in the SCN, which is in accordance with the light-dark cycle, is involved in circadian rhythm formation and that this periodic change is lost in elderly rats [17
]. In humans, a decrease in the number of VIP-expressing neurons
in the SCN has also been detected in both males (in the normal aging process) and females (in AD patients) [18
]. These reports suggest the important role of SCN in the development of CRSD in AD patients.
Orexin, a regulator of the sleep/wake rhythm, has been suggested to be involved in the development of AD. Orexin, which is a neuropeptide specifically expressed by neurons in the lateral hypothalamic area, is known to have various functions, such as the regulation of sleep/wake rhythm, eating behavior, locomotor activity and the autonomic nervous system. The axons of orexin-producing neurons are projected to the entire central nervous system, with the exception of the cerebellum. In the hypothalamus, these axons are projected to nuclei associated with eating behavior, such as the arcuate nucleus and ventromedial nucleus. Outside the hypothalamus, they are densely projected to the locus ceruleus, raphe nucleus (origin of monoaminergic neurons), tuberomammillary nucleus (origin of histaminergic neurons), lateral dorsal tegmental nucleus and pedunculopontine tegmental nucleus (origins of cholinergic neurons).
Monoaminergic and histaminergic neurons are known to be most active during waking, less active during non-REM sleep, and almost silent during REM sleep [19
]. These neurons are also projected to the thalamus and cerebral cortex, and a role in the maintenance of arousal. Cholinergic neurons are divided into two types: those activated during waking and REM sleep and those activated only during REM sleep [19
]. These facts suggest a physiological role for orexin in the stabilization of the sleep and wake stages. A study using post-mortem brains showed a decreased number of orexin-expressing cells in AD patients and a decreased orexin level in cerebrospinal
]. Kang et al. demonstrated that orexin stimulates Aβ accumulation in brain interstitial fluid (ISF) in mice expressing human APP [21
]. Furthermore, this study suggested that the amount of ISF Aβ significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. These studies suggest the possibility that orexin and the sleep disorders are connected with the AD onset.
Melatonin, a hormone secreted by the pineal gland, is known to have a sleep-promoting effect and a core body temperature-lowering effect [22
]. In normal individuals, melatonin secretion is decreased during the day, rapidly increased during the night and reaches its peak during night sleep. Melatonin induces sleep by acting on the SCN and melatonin receptors expressed throughout the body. The blood melatonin level gradually decreases during the night with age and this decrease is more profound in the elderly [23
]. In AD patients, a decreased melatonin level compared with normal elderly subjects is observed in the cerebrospinal fluid, as well as in the blood [24
]. Melatonin is known to penetrate the brain-blood barrier and function as an antioxidant and a free radical scavenger. In AD patients, a decreased melatonin level leads to greater accumulation of oxidative stress compared to normal elderly subjects [27
]. This is supported by a study using a mouse model of AD, where the accumulation of oxidative stress led to increased Aβ deposition [28
]. It has also been demonstrated that treating 3xTG-AD mice with melatonin results in reduced Aβ deposition and reduced tau hyperphosphorylation [29
]. An in vitro
study has also demonstrated that melatonin prevents Aβ β-sheet formation and Aβ fiber formation [30
]. These findings indicate that melatonin is deeply involved in the development of AD and suggest the beneficial role of its antioxidative and neuro-protective effects in the prevention and treatment of AD.