Astrocytes as governing pathological drivers of neurovascular dysfunction in AD

星形胶质细胞是 AD 神经血管功能障碍的病理驱动因素

• 批准号: 10584240
• 负责人: Brian J Bacskai
• 金额: $ 53.41万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584240
• 关键词: APP-PS1; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Amyloidosis; Astrocytes; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; Calcium; Calcium Signaling; Cause of Death; Cells; Central Nervous System; Cerebrovascular Circulation; Chronic; Communication; Complex; Dementia; Deposition; Deterioration; Development; Disease; Etiology; Evolution; Excision; Functional disorder; Glutamates; Health; Health Benefit; Health protection; Homeostasis; Human; Hyperemia; Image; Imaging Device; Impaired cognition; Individual; Longevity; Maintenance; Mediating; Metabolic; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurologic; Neuronal Dysfunction; Neurons; Osmosis; Pathogenesis; Pathologic; Photic Stimulation; Play; Potassium; Preparation; Process; Regulation; Reporter; Role; Senile Plaques; Sleep; Synapses; Synaptic Transmission; System; Testing; Therapeutic; United States; Visual Cortex; Wakefulness; Waste Products; abeta oligomer; awake; blood-brain barrier function; experimental study; functional decline; improved; in vivo; in vivo calcium imaging; in vivo imaging; interstitial; mouse model; multiphoton imaging; multiphoton microscopy; network dysfunction; neuroinflammation; neurovascular; neurovascular coupling; neurovascular unit; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; prevent; restoration; sleep health; synaptic function; targeted treatment; therapeutic target; tool

Astrocytes as governing pathological drivers of neurovascular dysfunction in AD Abstract: Alzheimer’s Disease (AD) is a progressive and irreversible neurodegenerative disease, characterized by cognitive decline. The pathogenesis of AD is complex, and the etiology has yet to be fully elucidated. The pathological manifestations of AD involve amyloid (Abeta) plaques and neurofibrillary tangles (NFTs), as well as a significant synaptic loss and neuronal degeneration, and a neuroinflammatory process accompanied by microglial and astrocytic activation. Specifically, the role of astrocytes in AD is very limited, although their contribution is likely crucial in the initiation and progression of AD. Astrocytes undertake numerous fundamental functions for the general homeostasis of the central nervous system, maintaining normal brain activities, and are key players in aging and dementia. Astrocytes are vital for maintaining the health of the neurovascular unit such as (but not limited to): contributing to synaptic transmission, blood flow dynamics, neurovascular coupling, glutamate homeostasis, potassium homeostasis, osmotic regulation, removal of interstitial waste products from the parenchyma, contributing to blood-brain barrier (BBB) function, sleep health and wakefulness. Astrocytes play an important role in functional hyperemia, in which local increases in blood flow meet the metabolic demands of increased neuronal activity. These findings highlight astrocytes as a central player within the neurovascular unit. Astrocytes demonstrate functional activity through calcium signaling, however, the role of astrocytic calcium signaling pathophysiology in neurovascular unit dysfunction remains poorly understood. We will test our governing hypothesis that astrocytic calcium signaling pathophysiology is a major governing pathological driver of neurovascular unit dysfunction in AD and an exciting and novel disease modifying therapeutic target. We have powerful in vivo tools and expertise to thoroughly test this hypothesis in vivo with multiphoton microscopy. We will image calcium concentrations and dynamics using genetically encoded calcium reporters targeted to astrocytes or neurons in all of the cellular compartments within single astrocytes, along with amyloid deposits, the vasculature, and neuronal calcium signaling to identify the mechanism of the astrocyte pathophysiology observed in mouse models of AD. We will interrogate the system through observations of plaque proximity, test the direct role of soluble Abeta oligomers, and use a functional hyperemia approach based on a visual stimulation paradigm to evaluate the deterioration of the function of the complete neurovascular unit. These experiments in total will determine which components of the neurovascular unit are compromised and when over the lifetime of the mice. Ultimately, this will guide decisions for the development of novel therapeutic approaches in AD.

星形胶质细胞是AD患者神经血管功能障碍的病理驱动因素 摘要： 阿尔茨海默病（AD）是一种进行性和不可逆的神经退行性疾病，其特征在于 认知能力下降AD的发病机制复杂，病因尚未完全阐明。的 AD的病理学表现包括淀粉样蛋白（Abeta）斑和神经纤维缠结（NFT 作为一个显着的突触损失和神经元变性，和神经炎症过程伴随着 小胶质细胞和星形胶质细胞活化。具体地说，星形胶质细胞在AD中的作用非常有限，尽管它们在AD中的作用非常有限。 在AD的发生和发展中可能起关键作用。星形胶质细胞承担着许多 中枢神经系统一般稳态的基本功能，维持正常的大脑 活动，是衰老和痴呆症的关键参与者。星形胶质细胞对于维持人类的健康至关重要。 神经血管单元，例如（但不限于）：促进突触传递，血流动力学， 神经血管偶联，谷氨酸稳态，钾稳态，渗透调节， 间质废物从实质，有助于血脑屏障（BBB）功能，睡眠健康 和清醒。星形胶质细胞在功能性充血中起重要作用，其中局部血液中的 血流满足增加的神经元活动的代谢需求。这些发现强调了星形胶质细胞作为一种 是神经血管单位的中枢。星形胶质细胞通过钙离子介导的功能活动 然而，星形胶质细胞钙信号传导的病理生理学在神经血管单位功能障碍中的作用 仍然知之甚少。我们将测试我们的主导假设，即星形胶质细胞钙信号传导 病理生理学是AD中神经血管单位功能障碍的主要支配病理驱动因素， 一个令人兴奋的新的疾病修饰治疗靶点。我们拥有强大的体内工具和专业知识 用多光子显微镜在体内彻底检验这一假设。我们会将钙浓度 和动力学使用基因编码的钙报告靶向星形胶质细胞或神经元在所有的 单个星形胶质细胞内的细胞区室，沿着有淀粉样沉积物、血管系统和神经元 钙信号转导，以确定在小鼠模型中观察到的星形胶质细胞病理生理学机制。 AD.我们将通过观察斑块接近度来询问系统，测试可溶性蛋白的直接作用。 Abeta寡聚体，并使用基于视觉刺激范例的功能性充血方法来评估 整个神经血管单位功能的退化。这些实验将决定 神经血管单元的哪些成分受损以及在小鼠的一生中何时受损。 最终，这将指导AD新治疗方法的开发决策。