Article

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

Department of Neurology, Washington University, St. Louis, MO 63110, USA.
Science (Impact Factor: 33.61). 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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    • "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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