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

周细胞作为代谢哨兵控制健康和阿尔茨海默氏病的脑血流

• 批准号: 10241247
• 负责人: Thomas A Longden
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10241247
• 关键词: Actins; Acute; Adenosine Triphosphate; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; American; Astrocytes; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Diseases; Calcium; Calcium Channel; Caliber; Cells; Cerebrovascular Circulation; Cerebrum; Coupling; Data; Dementia; Development; Disease Progression; Electrophysiology (science); Elements; Endothelial Cells; Energy Supply; Ensure; Event; Fatigue; Foundations; Functional disorder; Gap Junctions; Glucose; Health; Hemorrhage; Hyperemia; Hyperglycemia; Impaired cognition; Impairment; Ion Channel; Lead; Link; Measures; Mediating; Metabolic; Metabolism; Molecular; Mus; Muscle relaxation phase; Neuroglia; Neuronal Dysfunction; Neurons; Oxygen; Pathologic; Pericytes; Physiology; Population; Positioning Attribute; Potassium; Process; Protocols documentation; Publishing; Regulation; Relaxation; Role; SLC2A1 gene; Sentinel; Signal Transduction; Slice; Smooth Muscle; Testing; Therapeutic Intervention; Time; Trees; Work; arteriole; base; brain cell; brain metabolism; brain parenchyma; capillary bed; cerebral capillary; deprivation; experimental study; falls; glucose metabolism; mind control; mouse model; multiphoton imaging; neurovascular coupling; novel; novel therapeutics; parenchymal arterioles; patch clamp; promoter; relating to nervous system; response; sugar; targeted treatment; voltage

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.

神经元缺乏能量存储，因此它们的持续功能取决于能量的传递 血液中的底物。因此，精确控制脑血流对于神经元必不可少 健康。但是，调节血液流过大脑的机制仍然存在 不清楚。促进我们对这一过程的理解至关重要，因为它越来越受到赞赏 脑血流的破坏是阿尔茨海默氏病中最早的病理事件之一， 可能是疾病进展的关键因素。那，促进我们的理解 正常生理学中血流控制机制及其在上下文中的破坏 在阿尔茨海默氏病中，可能揭示了治疗干预的新颖和急需的靶标。 周细胞是位于脑毛细血管上的壁细胞，在内皮细胞和 星形胶质细胞终身。人们认为这些细胞有助于控制脑血流，但 缺乏机械细节。基于本提案中的初步数据，我们海报 周细胞是理想位置的，等效于充当大脑控制的代谢前哨 特别是，我们首次表明急性孤立的脑周细胞具有 功能性KATP通道，我们证明这些通道是响应葡萄糖耗竭的响应而开放的 引起收缩毛细血管周细胞和上游动脉平滑肌，放松。这 驱动毛细管和动脉词典，并增加脑血流。这有很大的 局部葡萄糖，对了解大脑中血流的控制的影响 已知浓度在神经元活性期间会瞬时降低。我们的数据提供了 这种现象的解释 - 神经葡萄糖利用率，周细胞的增加 感觉下降的局部浓度会触发KATP介导的电信号过度溶质 那样放松两个周周的人和上游艺术家平滑肌。这增加了血液 流量以补偿葡萄糖的局部减少，从而保护脑代谢。 令人惊讶的是，这种周围代谢 - 电动耦合机制在 阿尔茨海默氏病的小鼠模型，表明该血流控制机制的丧失 可能导致神经元能量需求与供应之间的不匹配，导致神经元 功能障碍和认知能力下降。将这些发现作为跳板，我们建议确定 整个周围的Katp通道的分子组成和代谢调节 脑。我们将定义与周围KATP通道控制血液的确切机制 流动，我们将确定周围控制脑血流的机制 在阿尔茨海默氏病中受到干扰。