Summary: Brain capillary Piezo1 ion channels and blood flow regulation in Alzheimer’s Disease Brain capillaries are the smallest blood vessels in the brain and are crucial in sensing the metabolic needs of active neurons and responding to these needs by supplying more blood. Notably, this function is impaired during neurodegenerative diseases such as Alzheimer’s disease. Not only that capillary sensing is impaired during Alzheimer’s disease, vascular stiffness and complete disruption of capillary blood flow, referred to as capillary stalling, have been observed in mouse models of Alzheimer’s disease. Given that capillary stalling disrupts the hemodynamic forces that capillaries are exposed to, it is important to understand whether Alzheimer’s disease associates with altered mechano-sensing abilities. We recently discovered that the protein Piezo1 is a mechanosensor in brain capillaries. Here, we test the overall hypothesis that altered Piezo1 channel activity is involved in the reduction of brain blood flow in Alzheimer’s disease. We further speculate that tuning Piezo1 activity will improve cerebral blood flow. We will investigate the contribution of endothelial Piezo1 channels to capillary stalling and blood flow reductions in a mouse model of Alzheimer’s disease. Using capillary endothelial cells from wild-type and Alzheimer’s disease mice, we will employ innovative electrophysiological and molecular approaches to assess whether Piezo1 ion channel expression and function are altered during Alzheimer’s disease. In the second aim, we will utilize in vivo high-resolution, two-photon microscopy to investigate capillary stalling and blood flow changes in Alzheimer’s disease mice while pharmacologically manipulating Piezo1 channels. This novel work could lead to new therapeutic strategies not previously tested.