¹ Department of Neurology, Washington University, St. Louis, MO 63110, USA.

² Department of Neurology, Washington University, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.; Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110, USA.

3 Department of Neurology, Washington University, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.

4 Sleep and Circadian Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA 94304, USA.

5 Department of Neurology, Washington University, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.; Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110, USA.; Department of Developmental Biology, Washington University, St. Louis, MO 63110, USA.

^* To whom correspondence should be addressed.
David M. Holtzman , E-mail: holtzman@neuro.wustl.edu

Amyloid- (A) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease (AD). The factors regulating this process are only partly understood. A aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of A. Using in vivo microdialysis in mice, we found that ISF A levels correlated with wakefulness. ISF A levels 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, A plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of AD.