Beta adrenergic receptor-dependent regulation of leukocytes in acute cardiac injury

摘要 作为一种神经退行性疾病，在美国和全世界每年都有越来越多的人受到影响， 阿尔茨海默病(AD)的特点是大脑皮质和海马区的一系列病理生理特征， 最终导致认知功能障碍和痴呆症。重要的是，虽然AD的频率随着 随着人口老龄化，缺乏有效的治疗选择来减缓发展或进展 这一疾病将在未来给社会带来巨大的经济和医疗负担 几十年来，这些患者及其主要照顾者的生活质量下降。了解 促成这种疾病发展的因素对于使一系列 以缓解老龄化人口中日益严重的危机。神经性炎症被认为是 与AD的发展和AD相关的病理生理学有关，免疫细胞在其中发挥作用 进程。外周白细胞被认为参与了这种神经炎性反应和 影响AD相关病理生理学的发展，尽管它们在其中发挥作用的程度 这一过程仍不确定。因此，我们的目标是描述外周血白细胞在大脑皮质中的聚集。 阿尔茨海默病模型中的海马区朝着调节其功能的新疗法的发展 对AD相关病理生理学的反应性。我们最近的研究表明，删除白细胞- β-2AR的表达导致免疫细胞定位和损伤反应性的改变。值得注意的是，这些 这种作用是通过G蛋白偶联受体激酶(Grk)/β-arrestin(βARR)依赖的信号转导介导的，AS GRK/βARR偶联而非G蛋白偶联表达的β2AR能够恢复正常 白细胞参数。从翻译上讲，我们证明了对β2AR具有选择性的β阻断剂 在小鼠、人白细胞和淋巴系中对白细胞和损伤反应的相同分子效应 纸巾。与这些观察结果相关的是，研究报告了β阻滞剂对AD相关的有益影响 在人类和AD动物模型中的神经病理学，然而，外周血白细胞- 表达的β-2AR对这些影响尚不清楚。因此，我们的目标是确定白细胞是否表达 β-2AR通过调节白细胞聚集影响AD相关的病理生理进展 大脑的皮质和海马区。总体而言，我们假设炎性外周血白细胞 在疾病进展的不同时间点差异地被招募到皮质/海马区 β2AR的白细胞特异性缺失将减缓AD相关疾病的发生和进展 神经病理学。此外，我们假设GRK/βARR偏向的β2AR信号将特别负责 对于这些影响，代表了抑制AD相关进展的新的治疗方向 病理生理学。

Abstract As a neurodegenerative disease affecting a growing number of people in the U.S. and worldwide each year, Alzheimer's disease (AD) is marked by a series of pathophysiological features in the cortex and hippocampus, ultimately leading to cognitive dysfunction and dementia. Importantly, while the frequency of AD increases as the population ages, there is a lack of effective treatment options for mitigating the development or progression of this disease, which will lead to an enormous financial and healthcare burden on society in the coming decades as well as decreased quality of life for those patients and their primary caregivers. Understanding the contributing factors to the development of this disease is imperative to enable the development of an array of therapeutics to alleviate this growing crisis in the ageing population. Neuroinflammation is recognized to be associated with the development of AD and AD-related pathophysiology, and immune cells to play roles in this process. Peripheral leukocytes have been suggested to contribute to this neuroinflammatory response and impact the development of AD-related pathophysiology, although the extent to which they play a role in this process remains uncertain. Thus, we aim to characterize peripheral leukocyte accumulation in the cortical- hippocampal regions in a model of AD toward the development of novel therapeutics to modulate their responsiveness to AD-related pathophysiology. Our recent work has demonstrated that deletion of leukocyte- expressed β2AR leads to alterations in immune cell localization and responsiveness to injury. Notably, these effects were mediated via G protein-coupled receptor kinase (GRK)/β-arrestin (βarr)-dependent signaling, as expression of a GRK/βarr-coupled, but not a G protein-coupled, β2AR was capable of restoring normal leukocyte parameters. Translationally, we demonstrated that β-blockers with selectivity toward β2AR exert the same molecular effects on leukocytes and response to injury in mice and in human leukocytes and lymphoid tissues. In relation to these observations, studies have reported beneficial effects of β-blockers on AD-related neuropathology in humans and animal models of AD, however the specific impact of peripheral leukocyte- expressed β2AR on these effects is not known. Thus, we aim to determine whether leukocyte-expressed β2AR impacts the progression of AD-related pathophysiology via regulation of leukocyte accumulation in the cortical and hippocampal regions of the brain. Overall, we hypothesize that inflammatory peripheral leukocytes are differentially recruited into the cortex/hippocampus at different timepoints during disease progression and that leukocyte-specific deletion of β2AR will reduce the development and progression of AD-related neuropathology. Further, we hypothesize that GRK/βarr-biased β2AR signaling in particular will be responsible for these effects, representing a novel therapeutic direction in which to dampen the progression of AD-related pathophysiology.