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.

神经元缺乏能量储存，因此它们的持续功能依赖于能量的输送 血液中的底物。因此，精确控制脑血流量对于神经元 健康然而，大脑中血液流动的调节机制仍然存在， 不清楚进一步了解这一进程至关重要，因为人们越来越认识到， 脑血流的中断是阿尔茨海默病最早的病理事件之一， 并且可能是疾病进展的关键促成因素。因此，增进我们对 正常生理学中的血流控制机制，以及它们在环境中的破坏 阿尔茨海默病的研究，可能揭示新的和急需的治疗干预的目标。 周细胞是位于脑毛细血管上的壁细胞，介于内皮细胞和内皮细胞之间。 星形胶质细胞终足据认为，这些细胞有助于控制脑血流量， 缺乏机械细节。根据本提案中的初步数据，我们认为， 周细胞是理想的位置和装备，作为代谢哨兵在控制脑 血流具体来说，我们首次发现急性分离的脑周细胞具有 功能性KATP通道，我们证明，这些开放响应于消耗葡萄糖 引起毛细血管周细胞和上游小动脉平滑肌的收缩、舒张。这 驱动毛细血管和小动脉扩张，增加脑血流量。这具有深刻的 这对理解大脑中血液流动是如何控制的有重要意义， 已知浓度在神经元活动期间瞬时降低。我们的数据提供了 对这种现象的解释-在神经元葡萄糖利用增加的过程中，周细胞 感觉到局部浓度下降，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。这增加了血液 血流量，以弥补葡萄糖的局部减少，从而保护大脑代谢。 引人注目的是，这种周细胞代谢-电偶联机制在一个细胞周期中被严重破坏。 阿尔茨海默氏病的小鼠模型，表明这种血流控制机制的丧失 可能导致神经元能量需求和供应之间的不匹配， 功能障碍和认知能力下降。利用这些发现作为跳板，我们建议确定 整个过程中周细胞KATP通道的分子组成和代谢调节 个脑袋我们将定义参与周细胞KATP通道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， 在老年痴呆症中被破坏。