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

项目摘要 阿尔茨海默病(AD)的实验疗法在临床研究中的失败强调了需要 具有新作用机制的新治疗靶点。一种策略是着眼于身体的自然防御 机械装置。对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 在缺乏认知障碍的对照组中，有证据表明AD的已知病理标记物的年份。 与其询问升高的β-淀粉样蛋白和神经原纤维缠结是否对神经元功能和 生存，由于这一点已经被集体和反复地证明，一个更有趣的问题是，为什么 许多人都有正常的认知，尽管有这些病理性的异常？去甲肾上腺素(NE) 系统是认知功能、神经炎症和系统免疫系统的关键调节器。严重者 AD患者去甲肾上腺素神经元的变性可能在多个层面上导致了疾病的进展。肾上腺素能 小胶质细胞上的受体调节神经炎症，控制神经元功能的保护机制和 生死存亡。外周免疫细胞向大脑的迁移也受去甲肾上腺素的调节，可能在 AD患者。利用已建立的学习和记忆范式平台，转基因小鼠模型 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)， 和化学发生工具，以选择性地下调NE系统，恢复特定β的音调 肾上腺素能1和2受体亚型(ADRB1和ADRB2)，这一建议将确定去甲肾上腺素的作用 类AD认知缺陷、神经炎症和病理学中的受体亚型。随后的实验将 检测ADRB1或ADRB2的条件性KO对髓系细胞(如小胶质细胞)的功能影响 巨噬细胞，但不是神经元)，首先是在急性内毒素神经炎症模型中，然后是在病理学上， 阿尔茨海默病5XFAD小鼠模型的神经炎症和行为。体外培养平台将检查 肾上腺素能激动剂调节炎症反应的分子机制 ADRB1条件性KO转基因小鼠分离培养小鼠小胶质细胞中的寡聚体淀粉样β蛋白 或ADRB2。最后一组研究将确定外周血单核细胞募集到大脑中的作用 预防AD相关的病理和认知障碍，并将决定ADRB1中去甲肾上腺素的贡献 和ADRB2在这次招聘中。这些最终研究将使用尖端技术进行浓缩或枯竭 外周免疫细胞群，结合前面描述的行为平台，化学发生 定向下调去甲肾上腺素的工具，以及创新的脑、血、脾和脑的流式细胞术分析 骨髓中去甲肾上腺素调节对驻留小胶质细胞、系统免疫细胞和 将系统免疫细胞重新招募到大脑。在这里获得的结果将增加我们对 肾上腺素能系统在调节认知和中枢及外周炎症中的作用 识别新的机制途径来调节神经退行性疾病的这些功能。

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.