Amyloid- Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle

Department of Neurology, Washington University, St. Louis, MO 63110, USA.
Science (Impact Factor: 31.48). 09/2009; 326(5955):1005-7. DOI: 10.1126/science.1180962
Source: PubMed

ABSTRACT Amyloid-β (Aβ) accumulation in the brain extracellular space is a hallmark of Alzheimer’s disease. The factors regulating
this process are only partly understood. Aβ aggregation is a concentration-dependent process that is likely responsive to
changes in brain interstitial fluid (ISF) levels of Aβ. Using in vivo microdialysis in mice, we found that the amount of ISF
Aβ correlated with wakefulness. The amount of ISF Aβ also significantly increased during acute sleep deprivation and during
orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly
increased, and a dual orexin receptor antagonist decreased, Aβ plaque formation in amyloid precursor protein transgenic mice.
Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer’s disease.

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Available from: Jae-Eun Miller, Apr 27, 2014
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    • "Several animal studies have now provided plausible mechanistic bases for effects of sleep disturbance on neurodegenerative disease onset or progression as well. For instance, it was recently reported that in mice, interstitial fluid levels of β-amyloid are increased with both orexin administration and sleep deprivation (Kang et al. 2009), and one of the key functions of sleep may be to allow clearance from the brain of potentially toxic species including β-amyloid (Xie et al. 2013). Given such studies as well as the breadth of data indicating that loss of sleep and wake consolidation often precedes and predicts neurodegenerative disease (Schenck et al. 2013) (Abbott et al. 2005)(Lim et al. 2013a), scientists should now address whether non-pharmacological (Wennberg et al. 2013) or pharmacological (Wennberg et al. 2013) (Lyseng-Williamson 2012) sleep therapies can decrease the likelihood of disease onset through preservation of wake-active neuronal systems in the elderly population. "
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    ABSTRACT: Sleep/wake disturbance is a feature of almost all common age-related neurodegenerative diseases. Although the reason for this is unknown, it is likely that this inability to maintain sleep and wake states is in large part due to declines in the number and function of wake-active neurons, populations of cells that fire only during waking and are silent during sleep. Consistent with this, many of the brain regions that are most susceptible to neurodegeneration are those that are necessary for wake maintenance and alertness. In the present review, these wake-active populations are systematically assessed in terms of their observed pathology across aging and several neurodegenerative diseases, with implications for future research relating sleep and wake disturbances to aging and age-related neurodegeneration.
    SpringerPlus 12/2015; 4(1):25. DOI:10.1186/s40064-014-0777-6
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    • "Indeed, initially the pivotal role of orexins in short-term feeding was well documented (Sakurai et al., 1998; Dube et al., 1999; B€ ackeberg et al., 2002; Thorpe and Kotz, 2005; Xu et al., 2013). Other evidence linked orexins to metabolic regulation and thermogenesis (Kukkonen et al., 2002; Monda et al., 2004; Funato et al., 2009; Kukkonen, 2013), stress response (Huang et al., 2010; Gerashchenko et al., 2011; Kukkonen, 2013), circadian rhythms (Deboer et al., 2004; Pekala et al., 2011), the regulation of sleep/wakefulness (Gerashchenko et al., 2001; Inutsuka and Yamanaka, 2013; Mieda et al., 2013; de Lecea and Huertra, 2014), memory processing (Akbari et al., 2008; Selbach et al., 2010), pathogenesis of Alzheimer disease (Kang et al., 2009), and epilepsy (Doreulee et al., 2010). It was also demonstrated that orexins modulate arousal: specifically, rodents treated with orexins spend more time awake (Hagan et al., 1999; Piper et al., 2000), and manifest increased locomotor activity (Alexandre et al., 2013). "
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    • "The cardinal feature of AD is the extracellular deposition of proteinaceous amyloid-b fibrils as senile plaques [2] [3]. In fact, protein aggregation into amyloid fibrils is involved both in AD and other neurodegenerative diseases such as Parkinson's, various dementias and prion diseases. "
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    ABSTRACT: Evidence indicates that inflammation, oxidative stress, and the disruption of normal conformation of proteins might be directly linked to Alzheimer’s Disease (AD). The present study was undertaken using literature data to find a possible drug to address the multiple disorders involved in AD-associated Aβ accumulation and plaque formation. We consider NOSH-aspirin a drug of choice for reducing the inflammatory areas in the brain (aspirin moiety), removing the noxious heavy metals from plaques (hydrogen sulfide), and increasing the oxygen supply to neurons since nitrogen oxide is a potent vasodilator and an anti-inflammatory agent. Several confirmatory data in literature and possible mechanisms for cellular defence as well as novel therapeutical pathways are discussed.
    Medical Hypotheses 03/2015; 84(3):262-267. DOI:10.1016/j.mehy.2015.01.008 · 1.07 Impact Factor
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