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 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 具有新型作用机理的新型热目标。一种策略是寻求人体的自然防御 机制。对AD患者和老年匹配对照的验尸研究使研究人员混淆了 多年来，在缺乏认知障碍的对照组中具有已知的AD病理标记的证据。 而不是询问升高的β-淀粉样蛋白和神经原纤维缠结是否对神经元功能有害和 生存，因为这已经集体，反复证明了，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？”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NE神经元的退化可能是许多级别的疾病进展。肾上腺素 小胶质细胞的受体调节神经炎症并控制神经元功能的受保护机制 生存。外周免疫细胞向大脑的迁移也受到NE音调的调节，可能会受到损害 广告患者。使用既定的学习和记忆范例的平台，小鼠的转基因模型 过表达的人突变淀粉样蛋白前体蛋白（APP+小鼠）或人突变型tau蛋白（PS19小鼠）， 以及在特定beta上恢复音调的选择性下调NE系统的化学遗传学工具 肾上腺素1和2受体亚型（ADRB1和ADRB2），该建议将确定去甲肾上腺素能的作用 广告样认知缺陷，神经炎症和病理学中的受体亚型。随后的实验将 检查髓样谱系细胞中ADRB1或ADRB2条件KO的功能后果（例如，小胶质细胞 和巨噬细胞，但不是神经元），首先是在神经炎症的急性LPS模型中，然后是病理学， AD的5xFAD小鼠模型中的神经炎症和行为。体外文化平台将检查 肾上腺激动剂对LPS或 来自转基因小鼠的孤立的原代小胶质细胞培养物中的低聚淀粉样β，具有ADRB1的条件KO 或ADRB2。最后一组研究将确定向大脑外周单核细胞募集到大脑中的作用 预防与广告相关的病理和认知定义，并将确定NE音调对ADRB1的贡献 和ADRB2在此招聘中。这些最终研究将使用尖端技术来丰富或耗尽 周围免疫池种群，结合了先前描述的行为平台，化学遗传 针对NE音调靶向下调的工具，以及对大脑，血液，sleen和sleen和 骨髓以识别NE音调调制对居民小胶质细胞，全身免疫细胞和 将全身免疫细胞募集到大脑。这里获得的结果将增加我们对 肾上腺素系统在调节认知，中心和周围感染中的作用，并将领导 识别新型机械途径以调节神经退行性疾病中的这些功能。