Modulating blood flow and metabolism in Alzheimer's Disease models

ABSTRACT This project will develop and apply new intravital microscopy techniques to gain greater insight into the putative benefits effects of gamma entrainment, a promising nonpharmacological neuromodulation technique for Alzheimer’s disease (AD) and other brain pathologies. Investigators recently demonstrated the powerful effects

of neuromodulation strategies for preserving synchronized neuronal activity in circuit pathways between the visual cortex, hippocampus, and pre-frontal cortex. Gamma entrainment using sensory stimulus (GENUS) is a simple, noninvasive gamma entrainment technique involving repeated exposure to a 40 Hz visual or auditory

stimulus. This method is easily translatable, and remarkably, experiments in preclinical animal models show that it effectively reduces Amyloid levels and synaptic degradation while evoking morphological changes and cytokine secretion from microglia. In some human patients, the technique has shown promise for reducing cognitive

decline. Ostensibly, the stimulus parameters require optimization to improve its efficacy in AD patients. The goal of this project is to gain a deeper understanding of how GENUS influences cerebral energy metabolism and microvascular hemodynamics. Advanced microscopy methods will be developed and applied to mouse models

of AD to nondisruptively characterize GENUS-related changes to cellular signaling, metabolism, and microvascular blood flow in the living brain with cellular resolution. By developing new microscopy techniques, we will explore how these indicators of metabolism and cerebral blood flow change in different regions of the

brain in response to GENUS neuromodulation. The project’s findings will improve our understanding of the technique’s operating mechanisms. By understanding how GENUS affects measurable changes of brain hemodynamics, the results will eventually guide strategies to optimize its utility in human patients. Ultimately,

the project’s findings will facilitate development of accessible, nonpharmacological methods to stem AD’s dramatically increasing global prevalence.