Role of beta adrenergic receptors in modulation of cognition, pathology and neuroinflammation in Alzheimer's Disease

β 肾上腺素能受体在阿尔茨海默病认知、病理和神经炎症调节中的作用

• 批准号: 9324078
• 负责人: Mehrdad Shamloo
• 金额: $ 19.95万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324078
• 关键词: ADRB1 gene; ADRB2 gene; Adrenergic Agents; Adrenergic Receptor; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Autopsy; Behavior; Behavioral; Blood; Bone Marrow; Brain; Cell Lineage; Cells; Clinical Research; Cognition; Cognitive deficits; Communication; Control Groups; Data; Defense Mechanisms; Development; Disease Progression; Failure; Flow Cytometry; Functional disorder; Gene Expression; Gene Expression Profiling; Human Amyloid Precursor Protein; Immune; Immune system; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Individual; Investigational Therapies; Knock-out; Learning; Memory; Microglia; Mus; Myelogenous; Myeloid Cells; Nerve Degeneration; Neuraxis; Neurofibrillary Tangles; Neuroimmune; Neurons; Norepinephrine; Pathologic; Pathology; Patients; Peripheral; Phagocytosis; Pharmacology; Phenotype; Play; Receptor Signaling; Recruitment Activity; Reporting; Research Personnel; Role; Signal Transduction; Specificity; Spleen; Symptoms; System; Technology; Testing; Transgenic Mice; Transgenic Model; Transgenic Organisms; Validation; aged; base; beta-adrenergic receptor; cell type; cognitive function; experimental study; in vivo; innovation; knock-down; locus ceruleus structure; macrophage; migration; monocyte; mouse model; neuroinflammation; new therapeutic target; noradrenergic; overexpression; pre-clinical; protein expression; receptor; response; restoration; tool; transmission process

Project Summary The failure of experimental therapeutics for Alzheimer’s disease (AD) in clinical studies emphasizes the need for validation of novel therapeutic targets with new mechanism of action. One strategy is to look to the body’s natural defense mechanisms. Postmortem studies of AD patients and aged-matched controls have confounded researchers for years with evidence of known pathological markers of AD in control groups with lack of cognitive impairments. Rather than asking if elevated beta-amyloid and neurofibrillary tangles are detrimental for neuronal function and survival, since this has collectively and repeatedly been demonstrated, a more interesting question is, “Why do many individuals have normal cognition, despite these pathological abnormalities?” The noradrenergic (NE) system is a key modulator of cognitive function, neuroinflammation and the systemic immune system. Severe degeneration of NE neurons in AD patients may underlie disease progression at many levels. Adrenergic receptors on microglia play critical roles in regulating neuroinflammation and governing protective mechanisms for neuronal function and survival. Migration of peripheral immune cells to the brain is also regulated by NE tone and may be impaired in AD patients. This proposal will determine the role of NE and beta adrenergic 1 and 2 receptor subtypes (ADRB1 and ADRB2) in AD-like cognitive deficits, neuroinflammation, and pathology using a platform of well-established learning and memory paradigms, transgenic models of mice overexpressing human amyloid precursor protein, and DREADD technology specifically targeting NE neurons in the locus ceruleus to reduce NE tone followed by restoration of tone at ADRB1 and ADRB2 with selective pharmacology. Innovative flow cytometry analysis of brain, blood, spleen and bone marrow will identify effects of modulation of NE tone on resident microglia, systemic immune cells and recruitment of systemic immune cells to the brain. Development of transgenic mice in which ADRB1 and ADRB2 can be conditionally deleted in myeloid lineage cells (e.g., microglia and macrophages, but not neurons) will enable the exploration of the cell-type and receptor subtype specificity of previously described effects of NE in modulation of AD-related behavior and pathophysiology in vivo. Subsequent experiments using an in vitro culture platform of isolated microglia/macrophages from transgenic and wildtype mice, with the ability to conditionally delete ADRB1 and ADRB2, will examine the receptor subtype dependent effects of NE on microglia/macrophage proliferation and phagocytosis.

项目摘要 临床研究中实验疗法对阿尔茨海默氏病（AD）的失败强调了需要 用新的作用机理对新型热目标的验证。一种策略是看身体的自然 国防机制。 AD患者和老年匹配对照的死后研究已经混淆 多年来的研究人员拥有缺乏认知的对照组中AD的已知病理标记的证据 障碍。而不是询问升高的β-淀粉样蛋白和神经原纤维缠结是否有害于神经元 功能和生存，因为这已经集体并反复证明，所以一个更有趣的问题 是，“为什么许多人有正常的认知，这些病理异常会吗？”这 NERADRENERAGIC（NE）系统是认知功能，神经炎症和全身免疫的关键调节剂 系统。 AD患者NE神经元的严重变性可能是疾病进展的许多水平。 小胶质细胞上的肾上腺素受体在控制神经炎症和管理受保护方面起关键作用 神经元功能和生存的机制。外周免疫细胞向大脑的迁移也受到调节 通过NE音调，AD患者可能会受到损害。 该建议将确定NE和Beta肾上腺素1和2受体亚型的作用（ADRB1和ADRB2） 在类似广告的认知缺陷，神经炎症和病理学中，使用了公认的学习平台 过表达人淀粉样前体蛋白的小鼠的记忆范例，转基因模型和dreadd 技术专门针对Ceruleus中的NE神经元以减少NE音调，然后恢复 具有选择性药理的ADRB1和ADRB2的音调。大脑，血液的创新流式细胞仪分析 脾脏和骨髓将确定NE音调调制对居民小胶质细胞的影响，全身免疫 细胞和全身免疫细胞向大脑的募集。 在髓样谱系中有条件地删除ADRB1和ADRB2的转基因小鼠的发展 细胞（例如，小胶质细胞和巨噬细胞，而不是神经元）将使细胞类型和接收器探索 NE在与AD相关行为调制和 体内病理生理学。随后使用孤立的体外培养平台进行的实验 来自转基因和野生型小鼠的小胶质细胞/巨噬细胞，能够有条件地删除ADRB1和 ADRB2，将检查NE对小胶质细胞/巨噬细胞增殖的接收器亚型依赖性影响 吞噬作用。