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: 10428632
• 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/10428632
• 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.

神经元缺乏能量储存，因此它们的持续功能依赖于能量的传递 因此，精确控制血液中的底物对于神经元至关重要。 然而，血液流经大脑的机制是受到调节的。 加深我们对这一过程的理解至关重要，因为它越来越受到重视。 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，从而增进我们的理解。 正常生理中血流控制的机制及其在背景下的破坏 阿尔茨海默病的研究可能会揭示新的且急需的治疗干预目标。 周细胞是位于脑毛细血管上的壁细胞，介于内皮细胞和 人们认为这些细胞有助于控制脑血流，但 根据该提案中的初步数据，我们认为缺乏机制细节。 周细胞的位置和装备非常理想，可以充当控制大脑的代谢哨兵 具体来说，我们首次证明了急性分离的大脑周细胞具有血流。 功能性 KATP 通道，我们证明这些通道会响应葡萄糖的消耗而打开 引起毛细血管周细胞收缩，以及上游小动脉平滑肌松弛。 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。 对于理解大脑中的血流如何控制（如局部葡萄糖）的影响 我们的数据表明，神经活动期间浓度会短暂降低。 这种现象的解释——在神经元葡萄糖利用率增加期间，周细胞 感知局部浓度下降，触发 KATP 介导的超极化电信号 放松周细胞本身和上游小动脉平滑肌这会增加血液。 流量来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，这种周细胞代谢-电耦合机制在 阿尔茨海默病小鼠模型，表明这种血流控制机制的丧失 可能会导致神经能量需求和供应之间的不匹配，从而导致神经能量 我们建议以这些发现为跳板来确定功能障碍和认知能力下降。 整个周细胞中 KATP 通道的分子组成和代谢调节 我们将定义周细胞 KATP 通道控制血液的精确机制。 流，我们将确定周细胞控制脑血流的机制 在阿尔茨海默病中被破坏。