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

项目摘要 阿尔茨海默病(AD)是最常见的老年性痴呆，占进行性认知障碍的比例 在美国，大约580万人的生活质量受到损害和影响。广告是 以神经炎症和小胶质细胞为特征的疾病在早期和晚期都有复杂的作用。 疾病。AD的特点还包括去甲肾上腺素(NE)信号的失调，退行性变 蓝斑(LC)去甲肾上腺素能神经元和进一步改变正常睡眠模式的睡眠障碍 Ne放行。通过β-2肾上腺素能受体(β-2-Ars)传递的信号已被证明具有抗炎和 改变阿尔茨海默病背景下的小胶质细胞行为，尽管其对AD病理的影响一直存在争议和 去甲肾上腺素对小胶质细胞的信号转导细节尚未明确。在这项补充建议中，我们将建立在 在亲代RO1中，我们发现内源性去甲肾上腺素通过 小胶质细胞β2受体减小了小胶质细胞杆的大小，并抑制了小胶质细胞对大脑的监视，限制了 小胶质细胞与神经元的相互作用和削弱经验依赖的可塑性。基于这项工作，我们 我相信随着觉醒状态波动的NE释放的正常模式允许小胶质细胞循环 通过“主动”和“被动”两种状态。当由于LC神经元变性或睡眠而导致NE释放迟钝时 在AD中，小胶质细胞不再在这些不同的状态中循环。这改变了他们的行为和影响 它们能够与淀粉样蛋白沉积相互作用，保护突触不被消除，并适当地对 它们周围环境中的线索。本附录中提供的工作将生成初步数据，以说明β2 在阿尔茨海默病小鼠模型中，AR信号随着时间的推移而改变，以及这与AD病理的相关性。 我们还将确定β2 AR信号的长期周期性药物刺激如何改变小胶质细胞 动力学和AD病理学为我们使用小胶质细胞特异性敲除的未来实验奠定了基础 以测试小胶质细胞在这一背景下的作用。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，确定是否长期丢失小胶质细胞中的β-2 AR信号 改变炎症反应。这些目标与亲本R01的目标高度协同，并具有明确的 与AD的相关性。它们将共同为未来的赠款申请生成支持数据，该申请建立在我们广泛的基础上 小胶质细胞β-2受体周期性刺激对小胶质细胞维持至关重要的假说 在AD病理背景下有益的反应。

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.