Paper
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Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.
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Comments
University of Kentucky
The recent report by Kang et al. suggests not only that amyloid may serve an important role in sleep regulation, but also further highlights the need for additional studies on its physiological role. The study shows that amyloid is at least a biomarker of sleep, but it is interesting to note that it may also provide a mechanistic link mediating orexinergic signaling that pushes brain systems toward sleep. These findings are especially compelling considering other identified physiological effects of amyloid/APP, for example, Aβ feedback synaptic inhibition (Hsieh et al., 2006) or amyloid-enhanced potassium channel conductance (Furukawa et al., 1996). These physiological effects may be linked to slow wave sleep oscillations and neuronal quiescence (Vyazovskiy et al., 2009).
However, it is also important to note that there are likely to be multiple players in sleep regulation. For example, earlier work indicates BDNF and Homer1a also play roles (Faraguna et al., 2008; Mackiewicz et al., 2008), and it will be interesting to see what specific role amyloid may play in the molecular networks associated with sleep. Future studies combining multiple techniques (for instance, EEG, cognition, and microarray) may be particularly well suited for elucidating interactions among complex networks regulating sleep and the consequences of its disruption.
References:
Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron. 2006 Dec 7;52(5):831-43. PubMed.
Furukawa K, Barger SW, Blalock EM, Mattson MP. Activation of K+ channels and suppression of neuronal activity by secreted beta-amyloid-precursor protein. Nature. 1996 Jan 4;379(6560):74-8. PubMed.
Vyazovskiy VV, Olcese U, Lazimy YM, Faraguna U, Esser SK, Williams JC, Cirelli C, Tononi G. Cortical firing and sleep homeostasis. Neuron. 2009 Sep 24;63(6):865-78. PubMed.
Faraguna U, Vyazovskiy VV, Nelson AB, Tononi G, Cirelli C. A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep. J Neurosci. 2008 Apr 9;28(15):4088-95. PubMed.
Mackiewicz M, Paigen B, Naidoo N, Pack AI. Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely candidate. Physiol Genomics. 2008 Mar 14;33(1):91-9. PubMed.
View all comments by Eric BlalockUniversity of Toronto
In this work from Dave Holtzman’s lab, the influence of the sleep-wake cycle on Aβ metabolism was explored. The investigators found that brain interstitial fluid levels of Aβ in transgenic mice fluctuated over a 24-hour period with lower levels during sleep and higher levels during wakefulness. Moreover, sleep-depriving the mice caused an increase in plaque load, but this effect could be abolished by treating the mice with Almorexant, a receptor antagonist of orexin—a molecule regulating the sleep-wake cycle. Finally, the researchers also looked at human CSF Aβ levels and found similar alterations over the day. This study provides important new evidence that Aβ formation and plaque deposition can be controlled by affecting the sleep pattern. Also, the work adds a new perspective to the use of CSF Aβ as a diagnostic marker, as the reference values may have to be adjusted to the sampling timepoints.
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