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

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： 验证具有新作用机制的新治疗靶点。一种策略是寻找身体的自然 防御机制AD患者和年龄匹配对照的尸检研究混淆了 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病理标志物的证据。 损伤而不是问β-淀粉样蛋白和神经元缠结的升高是否对神经元有害， 功能和生存，因为这已经被集体和反复证明，一个更有趣的问题， “为什么许多人有正常的认知，尽管这些病理异常？”的 去甲肾上腺素能（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基础。 小胶质细胞上的肾上腺素能受体在调节神经炎症和调节保护性神经元中起关键作用。 神经元功能和存活的机制。外周免疫细胞向大脑的迁移也受到调节 在AD患者中可能受损。 该提案将确定NE和β肾上腺素能1和2受体亚型（ADRB 1和ADRB 2）的作用。 在AD样认知缺陷，神经炎症和病理学中使用完善的学习平台， 记忆范式、过表达人淀粉样前体蛋白的小鼠转基因模型和DREADD 特异性靶向蓝斑中NE神经元的技术，以降低NE张力，然后恢复NE神经元的功能。 在ADRB 1和ADRB 2上具有选择性药理学作用。创新的流式细胞仪分析大脑，血液， 脾和骨髓将鉴定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。 骨髓系ADRB 1和ADRB 2有条件缺失转基因小鼠的建立 细胞（例如，小胶质细胞和巨噬细胞，但不是神经元）将使探索的细胞类型和受体 先前描述的NE调节AD相关行为的作用的亚型特异性， 体内病理生理学随后的实验使用体外培养平台分离的 来自转基因和野生型小鼠的小胶质细胞/巨噬细胞，具有条件性缺失ADRB 1的能力， ADRB 2将检查NE对小胶质细胞/巨噬细胞增殖的受体亚型依赖性作用， 吞噬作用

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.