Alzheimer's disease (AD) is an incurable brain disease, distinguished by the progressive accumulation of toxic amyloid and tau protein aggregates that are partly due to impaired waste clearance by the glymphatic and meningeal lymphatic systems. We have recently shown that noninvasive Gamma ENtrainment Using Sensory stimuli (GENUS) to induce neural oscillations in the gamma frequency range (30-90 Hz) could ameliorate pathology in various AD mouse models. Mice subjected to GENUS regime exhibited positive effects on microglia, astrocytes and the brain vasculature as well as reduced accumulation of amyloid and hyperphosphorylated tau in respective amyloid and tauopathy mouse models. However, the impact of GENUS on the glymphatic/lymphatic systems in the clearance of amyloid and tau accumulation is not clear. We will use amyloid and tauopathy mouse models to determine whether and identify the mechanisms by which GENUS enhances paravascular fluid movement and thereby promotes meningeal lymphatic drainage and glymphatic clearance of brain toxic metabolites including those associated with amyloid and tau.

The glymphatic and meningeal lymphatic clearance systems play a critical role in the removal of toxic amyloid and tau burden associated with Alzheimer's disease (AD) from the brain. We recently found that application of GENUS, a noninvasive regime using patterned light and sound to elicit gamma entrainment, reduced the accumulation of amyloid and tau and ameliorated cognitive functions in multiple disease mouse models, but the beneficial effects by which GENUS potentially impacts the brain clearance system are not clear. We will identify the effects and potential mechanisms by which GENUS impacts the physiological, cellular, and molecular responses of and subsequent clearance of AD-associated toxic amyloid by the glymphatic and meningeal lymphatic systems.