The glymphatic system: sleep, waste and neurodegeneration at the crossroads of the CNS

While aging is the strongest risk factor for the development of Alzheimer’s disease, disruption of normal sleep patterns has long been associated with aging and more recently has been associated with the development of Alzheimer’s pathology. Recently, a brain-wide perivascular network termed the ‘glymphatic’ system, has been characterized that facilitates the clearance of interstitial solutes including amyloid beta and tau from the brain. Interestingly, this function was active primarily in the sleeping brain, and is impaired in both the aging and the post-traumatic brain, suggesting one possible basis for the link between aging, sleep disruption and neurodegenerative processes. New data from human clinical subjects suggests that changes in the in elements of the glymphatic system, including the astroglial water channel aquaporin-4 (AQP4) are associated with Alzheimer’s status and pathology, and neurocognitive decline. These findings suggest that glymphatic insufficiency may be one feature of the aging brain that renders it vulnerable to protein mis-aggregation in neurodegenerative conditions such as Alzheimer’s.

Every person knows from their own experience that sleep refreshes the mind and the lack of it leaves the mind murky. The basis for this restorative function of sleep has remained a persistent mystery of neuroscience since ancient times. However recent experimental studies have shown that when the brain goes to sleep, it shifts into a ‘cleaning mode’, recirculating the fluid that surrounds it (cerebrospinal fluid, CSF) back through the brain tissue along a pathway termed the ‘glymphatic system’ to clear away wastes that have accumulated between the brain’s cells throughout the waking day. This housekeeping function may be one of the key reasons for the evolution of sleep. One of the wastes that the glymphatic system clears out of the brain is the protein amyloid beta, which is made in the brain all the time, but begins to accumulate in patients with Alzheimer’s disease, the leading cause of dementia. This buildup of amyloid beta is believed to be one of the key steps in the onset of this terrible disease. More recent work shows that the glymphatic system begins to fail as the brain ages, slowing the clearance of the protein amyloid beta. Linking sleep, aging and neurodegeneration, this change may be one key factor that sets the stage for protein aggregation in the aging brain and may promote the development of Alzheimer’s disease.