The glymphatic system clears metabolic waste in the brain by exchanging the interstitial fluid (ISF) surrounding neurons with ‘clean’ cerebrospinal fluid (CSF). Two new studies show that neurons drive glymphatic clearance of waste, including pathogenic proteins such as amyloid. Noninvasive gamma sensory stimulation, which has already entered clinical trials for the treatment of Alzheimer disease (AD), was found to promote the clearance of amyloid via this mechanism.

Li-Feng Jiang-Xie and colleagues investigated the relationship between neuronal oscillations during sleep and glymphatic waste clearance. “Given that sleep problems and waste accumulation are frequently intertwined with neurodegenerative diseases, we hypothesized that exploring these two fundamental processes may shed some light on the pathophysiology of neurological disorders, such as AD,” explains Jiang-Xie.

In mice, extracellular electrophysiological recordings from the interstitial space of the hippocampus revealed large, rhythmic ionic fluctuations during sleep but not during wakefulness. These high-energy waves enhanced perfusion of a CSF tracer in the hippocampus, suggesting that the flux of ions in the ISF drives glymphatic function.

Spike recordings from hippocampal neurons revealed that the large waves of ions were driven by synchronized action potentials from local neurons. Perfusion of a CSF tracer into the brain parenchyma was disrupted by chemogenetic inhibition of neuronal activity, indicating that this activity drives glymphatic clearance.

“We discovered that the force driving brain clearance is the same force that generates neuronal oscillations during sleep,” states Jiang-Xie. “Our findings explain why sleep problems and waste accumulation are commonly observed in neurodegenerative diseases.”

Mitchell Murdock and colleagues showed that 40 Hz audio-visual stimulation enhanced glymphatic clearance of amyloid in a mouse model of AD. Previous studies had demonstrated that gamma stimulation attenuates AD pathology, but the underlying mechanism was unknown.

The authors found that gamma stimulation promoted glymphatic flow by increasing polarization of the water channel aquaporin 4 on astrocytic endfeet and dilating meningeal lymphatic vessels to facilitate ISF–CSF exchange. Murdock et al. also used an optical sensor to monitor changes in neuropeptide signalling in response to stimulation. In line with results from Jiang-Xie et al., their findings suggest that synchronized neuronal activity promotes glymphatic clearance, mediated by neuropeptide release.

“It will be interesting to see how sensory stimulation in clinical settings might be useful to attenuate disease progression,” concludes Murdock. “Ongoing clinical work supports further investigation of noninvasive sensory stimulation as a disease-modifying therapeutic for AD.”