Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.
Amyloid-beta (Abeta) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta 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, Abeta 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.
Department of Neurology, Washington University, St. Louis, MO 63110, USA.
Jae-Eun
JE
Kang
Miranda M
MM
Lim
Randall J
RJ
Bateman
James J
JJ
Lee
Liam P
LP
Smyth
John R
JR
Cirrito
Nobuhiro
N
Fujiki
Seiji
S
Nishino
David M
DM
Holtzman
D000081:Acetamides / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000008:administration & dosage / Q000378:metabolism*; D064446:Orexin Receptors; D000068797:Orexins; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism; D015398:Signal Transduction; D012890:Sleep; D012892:Sleep Deprivation; D014851:Wakefulness
D000081:Acetamides; D016229:Amyloid beta-Peptides; D000954:Antigens, Surface; C501103:Cd200r1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C519150:almorexant