7 March 2024 | Mitchell H. Murdock, Cheng-Yi Yang, Na Sun, Ping-Chieh Pao, Cristina Blanco-Duque, Martin C. Kahn, TaeHyun Kim, Nicolas S. Lavoie, Mathews B. Victor, Md Rezaur Islam, Fabiola Galiana, Noelle Leary, Sidney Wang, Adele Bubnys, Emily Ma, Leyla A. Akay, Madison Snee, Yong Qian, Cuixin Lai, Michelle M. McCarthy, Nancy Kopel, Manolis Kellis, Kyril D. Piatkevich, Edward S. Boyden & Li-Huei Tsai
Multisensory gamma stimulation enhances glymphatic clearance of amyloid in Alzheimer's disease models. This study demonstrates that multisensory 40 Hz stimulation increases cerebrospinal fluid (CSF) influx and interstitial fluid (ISF) efflux in the cortex of 5XFAD mice, a model of Alzheimer's disease. The influx of CSF was associated with increased aquaporin-4 (AQP4) polarization along astrocytic endfeet and dilation of meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished amyloid removal by multisensory 40 Hz stimulation. The study found that vasoactive intestinal peptide (VIP) interneurons regulate arterial pulsatility, which drives glymphatic clearance. Multisensory gamma stimulation increases arterial pulsatility, leading to enhanced CSF movement and amyloid clearance. The study also shows that gamma stimulation promotes AQP4 polarization along astrocytic endfeet, which is critical for glymphatic function. VIP neurons were found to mediate gamma-mediated glymphatic clearance, as chemogenetic inhibition of VIP neurons reduced amyloid clearance and arterial pulsatility. These findings suggest that multisensory gamma stimulation promotes glymphatic clearance by enhancing arterial pulsatility and AQP4 polarization, which are essential for the removal of amyloid from the brain. The study highlights the role of the glymphatic system in clearing metabolic waste, including amyloid, and suggests that noninvasive gamma stimulation could be a therapeutic approach for Alzheimer's disease.Multisensory gamma stimulation enhances glymphatic clearance of amyloid in Alzheimer's disease models. This study demonstrates that multisensory 40 Hz stimulation increases cerebrospinal fluid (CSF) influx and interstitial fluid (ISF) efflux in the cortex of 5XFAD mice, a model of Alzheimer's disease. The influx of CSF was associated with increased aquaporin-4 (AQP4) polarization along astrocytic endfeet and dilation of meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished amyloid removal by multisensory 40 Hz stimulation. The study found that vasoactive intestinal peptide (VIP) interneurons regulate arterial pulsatility, which drives glymphatic clearance. Multisensory gamma stimulation increases arterial pulsatility, leading to enhanced CSF movement and amyloid clearance. The study also shows that gamma stimulation promotes AQP4 polarization along astrocytic endfeet, which is critical for glymphatic function. VIP neurons were found to mediate gamma-mediated glymphatic clearance, as chemogenetic inhibition of VIP neurons reduced amyloid clearance and arterial pulsatility. These findings suggest that multisensory gamma stimulation promotes glymphatic clearance by enhancing arterial pulsatility and AQP4 polarization, which are essential for the removal of amyloid from the brain. The study highlights the role of the glymphatic system in clearing metabolic waste, including amyloid, and suggests that noninvasive gamma stimulation could be a therapeutic approach for Alzheimer's disease.