Multisensory gamma stimulation promotes glymphatic clearance of amyloid

The glymphatic movement of fluid through the brain powerfully clears metabolic waste. We observed multisensory 40 Hz stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer’s disease, which was associated with increased aquaporin-4 polarization along astrocytic endfeet, dilated meningeal lymphatic vessels, and amyloid accumulation in cervical lymph nodes. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signaling, we found VIP+ interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms to recruit the glymphatic system to remove brain amyloid. 6-month-old 5XFAD mice were presented with gamma stimulation or no stimulation for 60 minutes, allowed to rest for 60 minutes, then nuclei were prepared for snRNA-seq using 10X Genomics platform. Four replicates were prepared for mice receiving gamma stimulation and no stimulation control, and each replicate contained the cortices of three 6-month-old 5XFAD mice.