Multisensory gamma stimulation promotes glymphatic clearance of amyloid

• Published in: Nature (London) 2024-03, Vol.627 (8002), p.149-156
• Main Authors: Murdock, Mitchell H., Yang, Cheng-Yi, Sun, Na, Pao, Ping-Chieh, Blanco-Duque, Cristina, Kahn, Martin C., Kim, TaeHyun, Lavoie, Nicolas S., Victor, Matheus B., Islam, Md Rezaul, Galiana, Fabiola, Leary, Noelle, Wang, Sidney, Bubnys, Adele, Ma, Emily, Akay, Leyla A., Sneve, Madison, Qian, Yong, Lai, Cuixin, McCarthy, Michelle M., Kopell, Nancy, Kellis, Manolis, Piatkevich, Kiryl D., Boyden, Edward S., Tsai, Li-Huei
• Format: Article
• Language: English
• Subjects: 14/19; 14/69; 45/91; 631/378/1689/1283; 631/378/2607; 631/378/87; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid - metabolism; Animal models; Animals; Aquaporin 4; Aquaporins; Blood vessels; Brain; Brain - metabolism; Cerebrospinal fluid; Clearances; Efflux; Extracellular Fluid - metabolism; Genetic code; Glymphatic System - pathology; Humanities and Social Sciences; Interneurons; Lymphatic system; Metabolism; Metabolites; Mice; Microscopy; multidisciplinary; Neurodegenerative diseases; Peptides; Science; Science (multidisciplinary); Stimulation; Vasoactive agents; Vasoactive intestinal peptide
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-024-07132-6

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. Audio and visual stimulation at 40 Hz promote cerebrospinal and interstitial fluid flux in mouse brain and result in amyloid clearance via the glymphatic system in a mouse model of Alzheimer’s disease.