Deciphering the role of junctional adhesion molecule-A in neutrophil-driven inflammatory response in Alzheimer disease

越来越多的证据表明，阿尔茨海默病(AD)相关的炎症 在两个不同但相互关联的部分中进展：血液和大脑， 这意味着白细胞可能导致“大脑激活”，而脑部炎症则可能 通过炎性介质影响外周系统。AD主要是慢性的 导致神经退行性变和脑血管疾病的神经炎症成分 发炎。然而，最近的研究表明，与急性呼吸综合征有关的因素 炎性反应，中性粒细胞，有助于病理和认知功能障碍 广告。中性粒细胞为什么以及如何“侵入”受AD影响的大脑，并对正在进行的 神经退行性变在很大程度上仍是未知的。这项拟议的研究旨在阐明 调节脑内皮细胞-中性粒细胞相互作用的关键细胞和分子事件 这可能导致中性粒细胞重新聚集和血管和中性粒细胞闭塞。 导致阿尔茨海默病炎症过程加剧。我们的初步数据显示 交界性黏附分子-A(JAM-A)，一种紧密连接的分子，在炎症中 作为一种白细胞黏附分子，在阿尔茨海默病患者脑内皮细胞上调。 JAM-A的基因操作以及专门设计的JAM-A拮抗剂 多肽减少中性粒细胞浸润和中性粒细胞胞外陷阱(Net)的形成 阿尔茨海默病小鼠脑血管和脑实质中的表达和行为缺陷的减少 模特。因此，这项提议强调了JAM-A是如何驱动中性粒细胞依赖的 AD中的炎性反应，并明确提出了这样的假设：“JAM-A 在中性粒细胞募集和网络形成中发挥关键作用 阿尔茨海默病患者的炎症和血管损伤。具体地说，它将评估：a) 全局性JAM-A基因敲除如何影响血管和实质中性粒细胞聚集 和AD的行为结局，b)内皮细胞相关JAM-A对 阿尔茨海默病患者血管和实质中性粒细胞聚集与行为结局 JAM-A对AD和d的不良影响的细胞和分子机制 JAM-A拮抗肽对AD诱导的中性粒细胞聚集和转录因子的影响 行为缺陷。总的来说，这些研究将提供与 中性粒细胞聚集和Net的发生机制不仅与 而且还能传播到多个疾病状态。希望这将有助于阐明小说 治疗AD相关炎症的治疗策略。

Accumulating evidence suggests that Alzheimer’s disease (AD)-related inflammation progresses in two different but interrelated compartments: the blood and the brain, implying that leukocytes could lead to “brain activation,” while brain inflammation may impact the peripheral system by inflammatory mediators. AD has predominantly chronic neuroinflammation components that drive neurodegeneration and cerebrovascular inflammation. However, recent studies have revealed that factors involved in acute inflammatory response, neutrophils, contribute to pathology and cognitive impairment in AD. Why and how neutrophils “invade” the AD-affected brain and contribute to ongoing neurodegeneration is still largely unknown. The proposed study is designed to elucidate critical cellular and molecular events regulating brain endothelial cell-neutrophil interaction that can lead to neutrophil recruitment and occlusion of blood vessels and neutrophil driven exacerbation of inflammatory processes in AD. Our preliminary data indicate that junctional adhesion molecule-A (JAM-A), a tight junction molecule that in inflammation acts as a leukocyte adhesion molecule, is upregulated at the brain endothelium in AD. Genetic manipulation of JAM-A as well as a specifically designed JAM-A antagonist peptide reduced neutrophil infiltration and neutrophil extracellular traps (NETs) formation in brain blood vessels and parenchyma and reduced behavioral deficits in a mouse AD model. This proposal, therefore, highlights how JAM-A drives neutrophil-dependent inflammatory responses in AD and specifically addresses the hypothesis that, “JAM-A plays critical roles in neutrophil recruitment and NETs formation driving the inflammatory and vascular injury in AD conditions”. Specifically, it will evaluate: a) how a global JAM-A knockout affects vascular and parenchymal neutrophil accumulation and behavioral outcomes in AD, b) the impact of endothelial-associated JAM-A on vascular and parenchymal neutrophil accumulation and behavioral outcomes in AD, c) the cellular and molecular mechanisms underlying the adverse effects of JAM-A in AD and d) the effects of JAM-A antagonist peptides on AD-induced neutrophil accumulation and behavioral deficits. Collectively, these studies will provide new information related to the mechanisms of neutrophil accumulation and NETs occurrence that is relevant not only to AD but also to multiple disease states. Hopefully, this will help to elucidate novel therapeutic strategies for treatment of AD-associated inflammation.