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The Emerging Relationship Between Interstitial Fluid–Cerebrospinal Fluid Exchange, Amyloid-β, and Sleep

  • Erin L. Boespflug
    Affiliations
    Department of Neurology, Oregon Health & Science University, Portland, Oregon

    Advanced Imaging Research Center, Oregon Health & Science University, Portland, Oregon
    Search for articles by this author
  • Jeffrey J. Iliff
    Correspondence
    Address correspondence to Jeffrey J. Iliff, Ph.D., Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code L458, Portland, OR 97239.
    Affiliations
    Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, Oregon

    Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
    Search for articles by this author
Published:December 06, 2017DOI:https://doi.org/10.1016/j.biopsych.2017.11.031

      Abstract

      Amyloid-β (Aβ) plaques are a key histopathological hallmark of Alzheimer’s disease (AD), and soluble Aβ species are believed to play an important role in the clinical development of this disease. Emerging biomarker data demonstrate that Aβ plaque deposition begins decades before the onset of clinical symptoms, suggesting that understanding the biological determinants of the earliest steps in the development of AD pathology may provide key opportunities for AD treatment and prevention. Although a clinical association between sleep disruption and AD has long been appreciated, emerging clinical studies and insights from the basic neurosciences have shed important new light on how sleep and Aβ homeostasis may be connected in the setting of AD. Aβ, like many interstitial solutes, is cleared in part through the exchange of brain interstitial fluid and cerebrospinal fluid along a brain-wide network of perivascular pathways recently termed the glymphatic system. Glymphatic function is primarily a feature of the sleeping brain, rather than the waking brain, and is slowed in the aging and posttraumatic brain. These changes may underlie the diurnal fluctuations in interstitial and cerebrospinal fluid Aβ levels observed in both the rodent and the human. These and other emerging studies suggest that age-related sleep disruption may be one key factor that renders the aging brain vulnerable to Aβ deposition and the development of AD. If this is true, sleep may represent a key modifiable risk factor or therapeutic target in the preclinical phases of AD.

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