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

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.

Keywords: Alzheimer's; Aquaporin-4; Astrocytes; CSF; Cerebrospinal fluid; Glymphatic; Interstitial fluid; Perivascular; Sleep.

Figure 1. Relationship between sleep, aging and Aβ in the setting of Alzheimer’s disease

(A) Schematic depicting diurnal fluctuations in interstitial and CSF Aβ levels measured in mice(55, 98) and human subjects(55, 106), respectively. During waking, Aβ levels increase while during sleep Aβ levels decline. These changes are thought to be attributable to increased metabolic demand and slowed glymphatic Aβ clearance during waking and more rapid glymphatic Aβ clearance during sleep and reduced metabolic burden during slow wave sleep. In the setting of Aβ plaques, the amplitude of the diurnal Aβ fluctuation declines as interstitial Aβ is sequestered into insoluble plaques and is unavailable for glymphatic clearance(98, 106). (B) Aging, sleep disruption, and glymphatic pathway impairment may constitute a feed-forward cycle promoting Aβ plaque deposition in the aging brain. (1) Sleep disruption, particularly of slow wave sleep, and astrogliosis are frequent features of the aging brain. (2) Reduced slow wave activity impairs glymphatic Aβ clearance, which is greatest in the sleeping brain(67). (3) Metabolic demand increases with loss of slow wave sleep, increasing Aβ formation(120). (4) Astrogliosis associated with aging, small vessel disease, traumatic brain injury or amyloid plaques is associated with impaired glymphatic pathway function, perhaps via impairment of perivascular AQP4 localization(9, 10, 76, 121). (5) The presence of Aβ aggregates specifically inhibits slow wave activity(122).