Clearance systems at brain borders

Abstract

Submitted to the Department of Brain and Cognitive Sciences on May 8th, 2023 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Neuroscience.

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 novel genetically encoded sensor for vasoactive intestinal peptide (VIP), 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.