Role of beta-adrenergic receptors in modulation of cognition and central and peripheral immune systems in Alzheimer's disease

β-肾上腺素能受体在阿尔茨海默病认知及中枢和外周免疫系统调节中的作用

• 批准号: 9383638
• 负责人: Mehrdad Shamloo
• 金额: $ 51.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383638
• 关键词: ADRB1 gene; ADRB2 gene; Acute; Adoptive Transfer; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Astrocytes; Autopsy; Behavior; Behavioral; Blood; Bone Marrow; Brain; Cell Lineage; Cells; Chronic; Clinical Research; Cognition; Cognitive deficits; Communication; Control Groups; Data; Defense Mechanisms; Disease Progression; Failure; Flow Cytometry; Functional disorder; Gene Expression; Gene Expression Profiling; Human; Immune; Immune system; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Individual; Inflammation; Inflammatory Response; Investigational Therapies; Knock-out; Knowledge; Learning; Mediating; Memory; Microglia; Modeling; Molecular; Molecular Profiling; Mononuclear; Mus; Myelogenous; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroimmune; Neurons; Norepinephrine; Norepinephrine Receptors; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Phagocytes; Pharmacology; Phenotype; Play; Population; Process; Recruitment Activity; Regulation; Research Personnel; Role; Signal Transduction; Site; Specificity; Spleen; Symptoms; System; Tauopathies; Technology; Testing; Transgenic Mice; Transgenic Model; Transgenic Organisms; aged; base; beta-adrenergic receptor; cell type; cerebral amyloidosis; cognitive function; disorder prevention; experimental study; immunoregulation; in vivo; innovation; locus ceruleus structure; macrophage; migration; monocyte; mouse model; mutant; neuroinflammation; neuropathology; new therapeutic target; noradrenergic; norepinephrine system; novel; overexpression; pre-clinical; protein expression; receptor; repaired; response; restoration; tau Proteins; tau mutation; tool; transgenic model of alzheimer disease; transmission process

Project Summary The failure of experimental therapeutics for Alzheimer’s disease (AD) in clinical studies emphasizes the need for novel therapeutic targets with novel mechanisms 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 norepinephrine (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 regulate neuroinflammation and govern 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. Using a platform of established learning and memory paradigms, transgenic models of mice overexpressing human mutant amyloid precursor protein (APP+ mice) or human mutant tau protein (PS19 mice), and chemogenetic tools to selectively downmodulate the NE system with restoration of tone at specific beta adrenergic 1 and 2 receptor subtypes (ADRB1 and ADRB2), this proposal will determine the role of noradrenergic receptor subtypes in AD-like cognitive deficits, neuroinflammation, and pathology. Subsequent experiments will examine functional consequences of conditional KO of ADRB1 or ADRB2 in myeloid lineage cells (e.g., microglia and macrophages, but not neurons), first in an acute LPS model of neuroinflammation, and then on pathology, neuroinflammation and behavior in the 5XFAD mouse model of AD. An in vitro culture platform will examine molecular mechanisms through which adrenergic agonists modulate inflammation in response to LPS or oligomeric amyloid beta in isolated primary microglia cultures from transgenic mice with conditional KO of ADRB1 or ADRB2. A final set of studies will determine the role of recruitment of peripheral monocytes to the brain in prevention of AD-related pathology and cognitive deficits and will determine the contribution of NE tone at ADRB1 and ADRB2 on this recruitment. These final studies will use cutting edge technology for enriching or depleting peripheral immune cell populations, combined with previously described behavioral platforms, chemogenetic tools for targeted downmodulation of NE tone, and innovative flow cytometry analysis of brain, blood, spleen and bone marrow to identify effects of modulation of NE tone on resident microglia, systemic immune cells and recruitment of systemic immune cells to the brain. The results obtained here will increase our knowledge about the role of the adrenergic system in modulation of cognition and central and peripheral inflammation and will lead to identification of novel mechanistic pathways to modulate these functions in neurodegenerative disorders.

项目摘要 阿尔茨海默病（AD）的实验治疗在临床研究中的失败强调了以下需要： 具有新作用机制的新治疗靶点。一种策略是依靠身体的自然防御 机制等对AD患者和年龄匹配的对照组的尸检研究使研究人员感到困惑， 在没有认知障碍的对照组中，有证据表明AD的已知病理标志物存在多年。 而不是问β-淀粉样蛋白和神经元缠结是否对神经功能有害， 生存，因为这已经被集体和反复证明，一个更有趣的问题是，"为什么 许多人有正常的认知，尽管这些病理异常？"去甲肾上腺素（NE） 系统是认知功能、神经炎症和全身免疫系统的关键调节剂。严重 AD患者中NE神经元的变性可能是许多水平的疾病进展的基础。肾上腺素 小胶质细胞上的受体调节神经炎症并控制神经元功能的保护机制， 生存外周免疫细胞向脑的迁移也受NE张力的调节，并且可能在NE缺乏时受损。 AD患者。使用已建立的学习和记忆范例的平台，小鼠的转基因模型 过表达人突变淀粉样前体蛋白（APP+小鼠）或人突变tau蛋白（PS19小鼠）， 和化学发生学工具来选择性地下调NE系统， 肾上腺素能1和2受体亚型（ADRB 1和ADRB 2），这一建议将确定去甲肾上腺素能受体的作用。 受体亚型在AD样认知缺陷、神经炎症和病理学中的作用。后续实验将 检查骨髓谱系细胞中ADRB 1或ADRB 2的条件性KO的功能结果（例如，小胶质 和巨噬细胞，但不是神经元），首先在神经炎症的急性LPS模型中，然后在病理学上， 在AD的5XFAD小鼠模型中的神经炎症和行为。一个体外培养平台将检测 肾上腺素能激动剂通过其调节炎症对LPS的反应的分子机制，或 来自ADRB 1条件性KO转基因小鼠的分离的原代小胶质细胞培养物中的寡聚淀粉样蛋白β 或ADRB 2。最后一组研究将确定外周血单核细胞向脑的募集在脑缺血中的作用。 预防AD相关病理和认知缺陷，并将确定ADRB 1时NE张力的贡献 和ADRB2在这次招聘中。这些最后的研究将使用尖端技术， 外周免疫细胞群，结合先前描述的行为平台，化学遗传学 用于NE张力的靶向下调的工具，以及脑、血液、脾脏和 骨髓以鉴定NE张力的调节对常驻小胶质细胞、全身免疫细胞和 全身免疫细胞向大脑的募集。这里获得的结果将增加我们对以下方面的知识： 肾上腺素能系统在调节认知和中枢及外周炎症中的作用， 涉及鉴定调节神经变性疾病中这些功能的新的机制途径。