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

Abstract

Amyloid-β (Aβ) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease (AD). The factors regulating this process are only partly understood. Aβ aggregation is a concentration-dependent process that is likely to be dependent on changes in brain interstitial fluid (ISF) levels of Aβ. Using in vivo microdialysis, we found that ISF Aβ levels correlated with wakefulness. ISF Aβ levels also significantly increased during acute sleep deprivation and during orexin infusion, whereas they decreased with infusion of a dual orexin receptor antagonist. Importantly, 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 AD.Alzheimer's disease (AD) is the most common cause of dementia. The accumulation of the amyloid-β (Aβ) peptide in the brain extracellular space is a critical event in the pathogenesis of AD. Aβ is produced by neurons and secreted into the brain interstitial fluid (ISF). An initiating factor in AD pathogenesis occurs when soluble, monomeric Aβ undergoes a conformational change and converts into forms such as oligomers, protofibrils, and fibrils. The accumulation of these forms of Aβ is concentration-dependent and confers toxicity (1). Elucidating factors that regulate soluble Aβ levels is important for understanding AD pathogenesis. Synaptic activity regulates the release of Aβ from neurons into the ISF (2,3). How ISF Aβ is regulated by normal physiology is poorly understood.To investigate ISF Aβ metabolism, we monitored hippocampal Aβ levels using in vivo microdialysis in both wild-type mice and human APP transgenic (Tg2576) mice, which express a mutated form of human amyloid precursor protein (APP) (4). ISF Aβ was assessed in Tg2576 mice at 3 months of age, several months earlier than Aβ deposition begins. We found diurnal variation of ISF Aβ levels. Aβ levels were significantly increased during the dark period compared to the light period (Fig. 1A). ISF Aβ levels fluctuated over a 24-hour period with mean levels during the light period being ~75% of mean Aβ levels during the dark period (Fig. 1B). ISF Aβ levels were significantly correlated with the amount of time spent awake (Fig. 1, C-D). Conversely, ISF Aβ levels were negatively correlated with the amount of time spent

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

“…In both in vitro and in vivo experiments with activity-induced secretion, the concentration of extracellular A β remains in the picomolar range. This concentration range of A β was also measured in the ISF of mice subjected to a circadian rhythm, with more elevated levels when awake (Kang et al , 2009 ). Moreover, other authors reported that A β levels in the picomolar range enhanced synaptic plasticity and memory (Puzzo et al , 2008 ;Garcia -Osta and Alberini, 2009 ).…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Together, these findings indicate that high‐quality sleep can mitigate Alzheimer's disease pathology. A connection between Aβ and NREM sleep has been found in rodent models (Kang et al, 2009; Roh et al, 2012). Investigating the underlying mechanisms of sleep, a recent study discovered a sleep‐dependent role for the lymphatic system in Aβ clearance (Xie et al, 2013).…”

“…This results in enhanced clearance of Aβ and other compounds. Conversely, the waking brain state can contribute to accumulation of Aβ (Kang et al, 2009), specifically through a higher neurometabolic rate relative to NREM sleep (Buchsbaum et al, 1989). Neurons consume greater levels of oxygen and ATP during wakefulness (Braun et al, 1997; Dworak, McCarley, Kim, Kalinchuk, & Basheer, 2010), while NREM sleep is associated with reduced oxygen consumption and active replenishment of ATP levels (Braun et al, 1997; Dworak et al, 2010).…”

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

“…237 The 42-residue amyloid-b (Ab) protein fragment is produced through cleavages, by proteases of the secretase family, from the transmembrane amyloid precursor protein (APP). Upon its formation at the cell's plasma membrane, Ab becomes largely extracellular but can also be found in the cytoplasm.…”