Manipulating Neural Oscillations with Non-Invasive Sensory Stimulation for Alzheimer's Disease Intervention

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Alzheimer's disease (AD) is an incurable brain disorder, with a staggering human and financial cost in a rising aging population. The complexity of its pathophysiology has proven to be a daunting challenge in the development of effective pharmacological interventions. 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, cerebral vasculature, as well as reduced accumulation of amyloid and hyperphosphorylated tau in respective amyloid and tauopathy mouse models. However, the mechanisms by which GENUS impacts cell-cell interactions, in particular, interactions between neurons and microglia, are not clear. To this end, we will utilize a combination of AD mouse models and innovative iPSC 3D co-culture system to assess the role of microglia in modifying the GENUS response, focusing on the contributions of microglial AD risk genes, APOE and TREM2, in modulating the neuroimmune interactions in response to GENUS.