Pericytes as metabolic sentinels in the control of brain blood flow in health and Alzheimer's disease

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Neurons lack energy stores and thus their ongoing function is dependent on the delivery of energy substrates in the blood. Precise control of brain blood flow is therefore essential for neuronal health. However, the mechanisms through which blood flow through the brain is regulated remain unclear. Furthering our understanding of this process is critical, as it is increasingly appreciated that disruption of brain blood flow is one of the earliest pathological events in Alzheimer’s disease, and may be a key contributory factor to disease progression. Thus, advancing our understanding of the mechanisms of blood flow control in normal physiology, and their disruption in the context of Alzheimer’s disease, may reveal novel and much needed targets for therapeutic intervention. Pericytes are mural cells that reside on brain capillaries, interposed between endothelial cells and astrocytic endfeet. It is thought that these cells contribute to the control of brain blood flow but mechanistic details are lacking. Based on the preliminary data in this proposal, we posit that pericytes are ideally positioned and equipped to act as metabolic sentinels in the control of brain blood flow. Specifically, we show for the first time that acutely isolated brain pericytes possess functional KATP channels, and we demonstrate that these open in response to depletion of glucose to cause contractile capillary pericyte, and upstream arteriole smooth muscle, relaxation. This drives capillary and arteriole dilation and an increase in brain blood flow. This has profound implications for understanding how blood flow is controlled in the brain, as local glucose concentrations are known to transiently decrease during neuronal activity. Our data offer an explanation for this phenomenon—during increases in neuronal glucose utilization, pericytes sense falling local concentrations which triggers KATP-mediated hyperpolarizing electrical signals that relax both pericytes themselves and upstream arteriolar smooth muscle. This increases blood flow to compensate for the local decrease in glucose, thereby protecting brain metabolism. Strikingly, this pericyte metabolism-electrical coupling mechanism is profoundly disrupted in a mouse model of Alzheimer’s disease, suggesting that loss of this blood flow control mechanism may contribute to a mismatch between neuronal energy demand and supply, precipitating neuronal dysfunction and cognitive decline. Using these findings as a springboard, we propose to determine the molecular composition and metabolic regulation of KATP channels in pericytes throughout the brain. We will define the precise mechanisms that engage pericyte KATP channels to control blood flow, and we will determine the mechanisms through which pericyte control of brain blood flow is disrupted in Alzheimer’s disease.