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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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) 的必要性验证具有新作用机制的新治疗靶点的一种策略是关注身体的自然状态。 AD 患者和年龄匹配的对照者的死后研究混淆了防御机制。多年来，研究人员在缺乏认知能力的对照组中发现了已知的 AD 病理标志物而不是询问β-淀粉样蛋白升高和神经原纤维缠结是否会导致神经元疼痛。功能和生存，因为这已被集体反复证明，这是一个更有趣的问题是，“尽管存在这些病理异常，但为什么许多人具有正常的认知能力？” 去甲肾上腺素能 (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 AD 患者 NE 神经元的严重退化可能是多个层面疾病进展的基础。小胶质细胞上的肾上腺素能受体在调节神经炎症和控制保护性方面发挥着关键作用神经功能和存活的机制也受到调节。 NE 音调，在 AD 患者中可能会受到损害。该提案将确定 NE 和 β 肾上腺素能 1 和 2 受体亚型（ADRB1 和 ADRB2）的作用使用完善的学习平台来治疗 AD 样认知缺陷、神经炎症和病理学记忆范式、过度表达人类淀粉样前体蛋白的小鼠转基因模型和 DREADD 专门针对蓝斑中的 NE 神经元的技术，以降低 NE 音调，然后恢复通过创新的流式细胞术分析脑、血液、ADRB1 和 ADRB2。脾脏和骨髓将识别 NE 音调的调节对驻留小胶质细胞、全身免疫的影响细胞和向大脑招募全身免疫细胞。骨髓系中有条件删除ADRB1和ADRB2的转基因小鼠的研制细胞（例如小胶质细胞和巨噬细胞，但不是神经元）将能够探索细胞类型和受体先前描述的 NE 在 AD 相关行为调节中的作用的亚型特异性使用分离的体外培养平台进行后续实验。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/巨噬细胞增殖的受体亚型依赖性影响，吞噬作用。