Cerebral functional hyperemia responses induced by capillary NMDA receptors are disrupted by amyloid-beta accumulation

毛细血管 NMDA 受体诱导的脑功能性充血反应被β-淀粉样蛋白积累破坏

• 批准号: 9812254
• 负责人: Paulo W Pires
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-18 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812254
• 关键词: 3xTg-AD mouse; Abbreviations; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Astrocytes; Biological Assay; Biotinylation; Blood; Blood capillaries; Blood flow; Brain; Brain region; Capillary Endothelial Cell; Cations; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrum; Communication; Coupled; Data; Dementia; Deposition; Electrophysiology (science); Endothelial Cells; Functional disorder; Glutamates; Human; Hyperemia; Immunofluorescence Immunologic; Impairment; Ion Channel; Laser-Doppler Flowmetry; Lead; Ligation; Maintenance; Measures; Mediator of activation protein; Metabolic; Microscopy; Modeling; Molecular; Myography; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neuroglia; Neurons; Nutrient; Patients; Perfusion; Physiological; Population; Process; Quality of life; Receptor Activation; Regulation; Research Project Grants; Resolution; Role; Signal Transduction; Testing; Trees; Vasodilation; Wild Type Mouse; abeta accumulation; arteriole; blood perfusion; brain circulation; capillary bed; cerebral capillary; cerebrovascular; falls; foot; improved; in vivo; inward rectifier potassium channel; member; mouse model; neuron loss; neuronal metabolism; neurovascular coupling; novel; novel therapeutics; parenchymal arterioles; patch clamp; pressure; receptor function; receptor internalization; response; sensor; somatosensory

Project Summary Accumulation of the protein amyloid-β is a hallmark of the condition called cerebral amyloid angiopathy, and is observed in approximately 80% of patients with Alzheimer’s disease, a most prevalent cause of dementia. Although dementia is a consequence of loss of neurons, studies show that impairment in the control of blood flow to active regions of the brain occurs before neuronal death is evident. Neurons have a limited capacity to store energy and nutrients necessary for their optimal function, thus relying on the cerebral circulation for delivery of necessary nutrients. One hallmark of the brain circulation is its ability to remarkably control blood perfusion to regions of increased neuronal activity, a process known as functional hyperemia. This localized increase in blood perfusion to match neuronal activity is a consequence of neurovascular coupling (NVC), in which neurons, glial cells (mainly astrocytes) and endothelial cells (EC) act in concert to promote vasodilation of upstream arterioles, shunting blood to active neurons. Functional hyperemia and NVC are known to occur for more than a century, but most of its mediators and cellular effectors remain unknown. Active neurons release a plethora of transmitters that activates astrocytes, a type of non-neuronal cells in the brain. Astrocytes, on the other hand, emit projections that envelop cerebral capillaries, called astrocytic end-feet. Therefore, substances released from activated astrocytes can then act on cerebral capillary EC to signal to the vasculature the metabolic status of a particular neuronal population. Capillary EC do not possess contractile activity, thus control of blood perfusion through a capillary bed will fall on the contractile member of the cerebral microvascular tree: the upstream parenchymal arteriole. For capillary EC to cause dilation of upstream arterioles, it is necessary that a sensor in capillary EC initiates a signal that is rapidly transmitted to upstream arterioles. This project focuses on the effects of one of such signals, the N-Methyl-D-Aspartate receptor (NMDAR) and its role in generating a propagated vasodilatory response from the capillaries to arterioles in the brain. Further, studies proposed here will also investigate how amyloid-β can interfere in this essential process in the brain, as amyloid-β was shown to reduce NMDAR activity in neurons. Thus, it is possible that one of the mechanisms by which amyloid-β impairs NVC in patients with cerebral amyloid angiopathy is by reducing the activity of NMDAR in cerebral capillary EC.

项目摘要 蛋白质淀粉样蛋白-β的积累是该疾病的标志，称为脑淀粉样血管病，是 在大约80％的阿尔茨海默氏病患者中观察到，这是痴呆症的最普遍原因。 尽管痴呆症是神经元丧失的结果，但研究表明，控制血液的损害 在神经元死亡之前发生流向大脑的活跃区域。神经元的能力有限 将其最佳功能所需的能量和营养存储，因此依靠脑循环进行输送 必要的营养。大脑循环的一个标志是它可以明显控制血液灌注到 神经元活性增加的区域，这一过程称为功能性充血。这种局部增加的血液 与神经元活性相匹配的灌注是神经血管耦合（NVC）的结果，其中神经元，神经胶质 细胞（主要是星形胶质细胞）和内皮细胞（EC）协同作用，促进上游小动物的血管舒张， 将血液流向活性神经元。众所周知，功能性充血和NVC发生了一个多世纪 但是它的大多数介体和细胞效应仍然未知。活性神经元释放了很多发射器 激活星形胶质细胞，这是一种大脑中的一种非神经元细胞。另一方面，星形胶质细胞发出项目 那个包膜脑毛细血管，称为星形细胞末端。因此，从激活中释放的物质 然后，星形胶质细胞可以作用于脑毛细管EC，向脉管系统发出信号 神经元种群。毛细管EC不具有收缩活性，因此通过A控制血液灌注 毛细管床将落在脑微血管树的收缩成员上：上游实质 动脉。对于毛细管EC引起上游小动物的扩散，有必要在毛细管EC中使用传感器 启动迅速传播到上游动脉的信号。该项目着重于其中一个的影响 这样的信号，N-甲基-D-天冬氨酸受体（NMDAR）及其在产生传播的血管舒张中的作用 毛细血管对大脑中动脉的反应。此外，这里提出的研究还将研究 淀粉样蛋白β可以干扰大脑的这一基本过程，因为淀粉样蛋白β已显示可降低NMDAR活性 在神经元中。这是，淀粉样蛋白β损害NVC的一种机制之一可能是 脑淀粉样血管病是通过降低NMDAR在脑毛细管EC中的活性。