Mechanisms that regulate microglial dynamics in the context of plasticity (Supplement)

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是最常见的年龄相关性痴呆， 在美国，约有580万人的生活质量受损。AD是 以神经炎症和小胶质细胞为特征的神经胶质细胞在神经系统疾病的早期和晚期都具有复杂的作用。 疾病AD的特征还在于去甲肾上腺素（NE）信号传导的失调， 蓝斑（LC）中的去甲肾上腺素能神经元和睡眠障碍进一步改变了正常的 释放。通过β2肾上腺素能受体（β2 AR）的信号传导已被证明具有抗炎作用， 改变AD背景下的小胶质细胞行为，尽管其对AD病理学的影响一直存在争议， NE信号传导至小神经胶质细胞的细节尚未确定。在这份补充建议书中，我们会以 我们已经发现，通过内源性NE信号传导到小胶质细胞， 小胶质细胞β2 AR减少了小胶质细胞乔木的大小，并抑制了小胶质细胞对大脑的监视，限制了小胶质细胞的生长。 小胶质细胞与神经元的相互作用和损害经验依赖性可塑性。基于这项工作，我们 我相信NE释放的正常模式是作为唤醒状态的函数而波动的，这允许小胶质细胞循环 通过“主动”和“被动”状态。当NE释放由于LC神经元变性或睡眠而减弱时， 在AD中，小胶质细胞不再循环通过这些不同的状态。这改变了他们的行为和影响 它们与淀粉样蛋白沉积物相互作用的能力，保护突触免于消除，并对 环境中的线索。本增刊中提出的工作将产生初步数据，以显示β2 在AD小鼠模型中，AR信号随着时间的推移在小胶质细胞中发生变化，以及这与AD病理学的相关性。 我们还将确定β2 AR信号的长期周期性药理学刺激如何改变小胶质细胞 动力学和AD病理学为未来的实验奠定了基础，我们使用小胶质细胞特异性敲除 的β2 AR来测试小胶质细胞在这种情况下的贡献。最后，我们将使用这些小胶质细胞特异性β2 AR， KO小鼠，在没有AD病理的情况下，以确定小胶质细胞中β2 AR信号的长期丢失是否 改变炎症反应。这些目标与母体R01的目标高度协同， 与AD有关。他们将共同为未来的赠款申请生成支持数据， 假设小胶质细胞β2 AR的周期性刺激对于维持小胶质细胞β2 AR是关键的， 在AD病理学的背景下有益的反应。

Project Summary Alzheimer's disease (AD) is the most common age-related dementia, accounting for the progressive cognitive impairment and compromised life quality of approximately 5.8 million people in the United States. AD is characterized by neuroinflammation and microglia have a complex role in both the early and late stages of the disease. AD is also characterized by dysregulation of norepinephrine (NE) signaling, degeneration of noradrenergic neurons in the locus coeruleus (LC) and sleep disturbances that further alter normal patterns of NE release. Signaling through β2 adrenergic receptors (β2 ARs) has been shown to be anti-inflammatory and to alter microglial behavior in the context of AD, although its effects on AD pathology have been controversial and the details of NE signaling to microglia have not been defined. In this supplement proposal, we will build on the aims of the parent RO1 in which we have discovered that endogenous NE signaling to microglia through microglial β2 ARs reduces the size of the microglial arbor and inhibits microglial surveillance of the brain, limiting microglial interactions with neurons and impairing experience-dependent plasticity. Based on this work, we believe that the normal patterns of NE release that fluctuate as a function of arousal state allow microglia to cycle through “active” and “passive” states. When NE release is blunted due to LC neuron degeneration or sleep disruption in AD, microglia no longer cycle through these different states. This alters their behavior and impacts their ability to interact with amyloid deposits, protect synapses from elimination, and respond appropriately to cues in their environment. The work presented in this supplement will generate preliminary data to show how β2 AR signals are altered in microglia over time in a mouse model of AD, and how this correlates with AD pathology. We will also determine how long-term periodic pharmacological stimulation of β2 AR signaling alters microglial dynamics and AD pathology to set the stage for future experiments where we use microglial specific knock out of β2 ARs to test the contribution of microglia in this context. Lastly, we will use these microglial specific β2 AR KO mice, in the absence of AD pathology, to determine whether long-term loss of β2 AR signaling in microglia alters inflammatory responses. These aims are highly synergistic with those of the parent R01 and have clear relevance to AD. Together they will generate supporting data for a future grant application built on our broad hypothesis that cyclical stimulation of microglial β2 ARs is critical for the maintenance of microglial responses that are beneficial in the context of AD pathology.