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

神经元缺乏能量储存，因此它们正在进行的功能依赖于能量的传递 血液中的底物。因此，精确控制脑血流对神经元来说是至关重要的 健康。然而，血液流经大脑的调节机制仍然存在。 不清楚。增进我们对这一进程的理解是至关重要的，因为它日益受到重视 脑血流中断是阿尔茨海默病最早的病理事件之一， 并可能是疾病进展的关键因素。因此，推进我们的认识 正常生理中血流控制的机制，以及它们在环境中的破坏 对阿尔茨海默病的研究，可能揭示治疗干预的新的和急需的靶点。 周细胞是存在于脑毛细血管上的壁细胞，介于内皮细胞和 星形细胞的尾足。据认为，这些细胞有助于控制脑血流，但 缺乏机械性的细节。根据这份提案中的初步数据，我们假设 周细胞处于理想的位置和装备，在大脑控制中扮演代谢哨兵的角色。 血液流动。具体地说，我们首次展示了急性分离的脑周细胞拥有 功能性KATP通道，我们证明了这些通道是在葡萄糖耗尽时开放的 可引起毛细血管周细胞收缩，以及微动脉上游的平滑肌松弛。这 促进毛细血管和小动脉扩张，增加脑血流量。这具有深远的意义 对理解大脑中的血液流动是如何控制的，如局部葡萄糖 众所周知，在神经元活动期间，浓度会短暂下降。我们的数据提供了 对这一现象的解释--在神经元葡萄糖利用率增加的过程中，周细胞 感知局部浓度下降，触发KATP介导的超极化电信号 使周细胞本身和上游小动脉平滑肌松弛。这会增加血液 流动以补偿局部葡萄糖的减少，从而保护大脑的新陈代谢。 引人注目的是，这种周细胞新陈代谢-电耦合机制在一种 阿尔茨海默病的小鼠模型，表明这种血流控制机制的丧失 可能会导致神经元能量需求和供应之间的不匹配，从而促使神经元 功能障碍和认知能力下降。以这些发现为跳板，我们建议确定 周细胞KATP通道的分子组成和代谢调节 大脑。我们将定义利用周细胞KATP通道来控制血液的精确机制 我们将确定周细胞控制脑血流的机制 在阿尔茨海默氏症中受到干扰。

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.