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 神经血管功能障碍的病理驱动因素 抽象的： 阿尔茨海默病（AD）是一种进行性且不可逆的神经退行性疾病，其特征是 AD的发病机制复杂，病因尚未完全阐明。 AD 的病理表现还涉及淀粉样蛋白 (Abeta) 斑块和神经原纤维缠结 (NFT) 作为显着的突触损失和神经元变性，以及伴随的神经炎症过程 具体而言，星形胶质细胞在 AD 中的作用非常有限，尽管它们的作用非常有限。 星形胶质细胞在 AD 的发生和进展中发挥着重要作用。 中枢神经系统总体稳态的基本功能，维持正常的大脑 星形胶质细胞是衰老和痴呆的关键参与者，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）：有助于突触传递、血流动力学、 神经血管耦合，谷氨酸稳态，钾稳态，渗透压调节，去除 来自实质的间质废物，有助于血脑屏障（BBB）功能、睡眠健康 星形胶质细胞在功能性充血中发挥重要作用，其中血液局部增加。 这些发现强调了星形胶质细胞作为一种神经活动的代谢需求。 神经血管单元内的核心角色星形胶质细胞通过钙表现出功能活性。 然而，星形细胞钙信号传导病理生理学在神经血管单元功能障碍中的作用 我们仍然知之甚少，我们将检验我们的主导假设：星形细胞钙信号传导。 病理生理学是 AD 和神经血管单元功能障碍的主要病理驱动因素 我们拥有强大的体内工具和专业知识。 为了用多光子显微镜在体内彻底检验这一假设，我们将对钙浓度进行成像。 和动力学使用基因编码的钙生产者针对星形胶质细胞或神经元在所有 单个星形胶质细胞内的细胞区室，以及淀粉样蛋白沉积物、脉管系统和神经元 钙信号传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，测试可溶性的直接作用。 Abeta 寡聚物，并使用基于视觉刺激范式的功能性充血方法来评估 整个神经血管单元功能的恶化将决定这些实验的总和。 神经血管单元的哪些组成部分在小鼠的一生中何时受到损害。 最终，这将指导开发 AD 新型治疗方法的决策。