Multisensory gamma stimulation promotes glymphatic clearance of amyloid
Mitchell H. Murdock, Cheng-Yi Yang, Na Sun, Ping‐Chieh Pao, Cristina Blanco‐Duque, Martin C. Kahn, TaeHyun Kim, Nicolas Lavoie, Matheus B. Victor, Md. Rezaul Islam, Fabiola Galiana-Melendez, Noelle Leary, Sidney Wang, Adele Bubnys, Emily Ma, Leyla Anne Akay, Madison A. Sneve, Yong Qian, Cuixin Lai, Michelle M. McCarthy, Nancy Kopell, Manolis Kellis, Kiryl D. Piatkevich, Edward S. Boyden, Li‐Huei Tsai
Abstract
Abstract The glymphatic movement of fluid through the brain removes metabolic waste 1–4 . Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer’s disease 5–8 . Here we show that multisensory gamma 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. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.