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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要阿尔茨海默病 (AD) 的实验疗法在临床研究中的失败强调了对阿尔茨海默氏病 (AD) 的必要性具有新作用机制的新治疗靶点之一是关注人体的自然防御。 AD 患者和年龄匹配的对照组的尸检研究让研究人员感到困惑。多年来，在没有认知障碍的对照组中，有已知 AD 病理标志物的证据。与其问β-淀粉样蛋白和神经原纤维缠结升高是否对神经元功能造成困扰，生存，既然这一点已经被集体地、反复地证明，一个更有趣的问题是，“为什么尽管有这些病理异常，许多人的认知能力还是正常的？” 系统是认知功能、神经炎症和全身免疫系统的关键调节剂。 AD 患者的 NE 神经元变性可能是许多水平的疾病进展的基础。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外周免疫细胞向大脑的迁移也受到 NE 音调的调节，并且可能会受到损害。 AD 患者使用已建立的学习和记忆范例平台，建立小鼠转基因模型。过度表达人类突变淀粉样前体蛋白（APP+小鼠）或人类突变tau蛋白（PS19小鼠），和化学遗传学工具选择性下调 NE 系统，恢复特定 beta 的音调肾上腺素能 1 和 2 受体亚型（ADRB1 和 ADRB2），该提案将确定去甲肾上腺素能的作用 AD 样认知缺陷、神经炎症和病理学中的受体亚型。检查髓系细胞（例如小胶质细胞）中 ADRB1 或 ADRB2 条件性 KO 的功能后果巨噬细胞，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，体外培养平台将检查 AD 5XFAD 小鼠模型的神经炎症和行为。肾上腺素能激动剂调节炎症反应的分子机制条件性敲除 ADRB1 的转基因小鼠中分离的原代小胶质细胞培养物中的寡聚淀粉样蛋白或 ADRB2 的最后一组研究将确定外周单核细胞募集至大脑的作用。预防 AD 相关病理和认知缺陷，并将确定 NE 音调在 ADRB1 上的贡献和 ADRB2 在本次招募中的这些最终研究将使用尖端技术来丰富或耗尽。外周免疫细胞群，结合之前描述的行为平台、化学遗传学用于定向下调 NE 音调的工具，以及对脑、血液、脾脏和骨髓以确定 NE 音调调节对常驻小胶质细胞、全身免疫细胞和这里获得的结果将增加我们对大脑的全身免疫细胞的了解。肾上腺素能系统在认知调节以及中枢和外周炎症中的作用，并将导致识别新的机制途径来调节神经退行性疾病中的这些功能。