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

解读连接粘附分子-A 在阿尔茨海默病中性粒细胞驱动的炎症反应中的作用

基本信息

项目摘要

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.
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行:血液和大脑, 这意味着白细胞可能导致“大脑激活”,而大脑炎症可能 通过炎症介质影响外周系统。AD主要是慢性的 神经炎症成分驱动神经变性和脑血管 炎症然而,最近的研究表明,参与急性 炎症反应,中性粒细胞,有助于病理和认知障碍, AD.中性粒细胞为何以及如何“入侵”受AD影响的大脑并促成持续的 神经变性在很大程度上仍是未知的。这项研究旨在阐明 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募集和血管闭塞, 导致AD炎症过程恶化。我们的初步数据显示, 连接粘附分子-A(JAM-A)是一种紧密连接分子, 作为白细胞粘附分子,在AD中的脑内皮上调。 JAM-A的遗传操作以及专门设计的JAM-A拮抗剂 肽减少中性粒细胞浸润和中性粒细胞胞外陷阱(NETs)形成 在脑血管和脑实质中, 模型因此,这项提议突出了JAM-A如何驱动依赖于嗜中性粒细胞的 的炎症反应,并特别提出了假设,“JAM-A 在中性粒细胞募集和NET形成中起关键作用, 炎症和血管损伤”。具体来说,它将评估:a) JAM-A基因敲除如何影响血管和实质中性粒细胞聚集 B)内皮相关的JAM-A对AD的影响, AD患者的血管和实质中性粒细胞积聚和行为结果,c) JAM-A在AD中的不良作用的细胞和分子机制,和d) JAM-A拮抗剂肽对AD诱导的中性粒细胞积聚的作用, 行为缺陷总的来说,这些研究将提供有关 中性粒细胞积聚和NETs发生的机制不仅与 AD也与多种疾病状态有关。希望这将有助于阐明小说 治疗AD相关炎症的治疗策略。

项目成果

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ANUSKA V. ANDJELKOVIC-ZOCHOWSKA其他文献

ANUSKA V. ANDJELKOVIC-ZOCHOWSKA的其他文献

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{{ truncateString('ANUSKA V. ANDJELKOVIC-ZOCHOWSKA', 18)}}的其他基金

Molecular mechanism mediating apicobasal brain endothelial cells polarity in cerebral cavernous malformation type 3-lesion
脑海绵状血管瘤3型病变中顶基底层脑内皮细胞极性的分子机制
  • 批准号:
    10526456
  • 财政年份:
    2022
  • 资助金额:
    $ 65.85万
  • 项目类别:
The mechanism of blood brain barrier impairment in cerebral cavernous malformatio
脑海绵状血管瘤血脑屏障损伤的机制
  • 批准号:
    8166264
  • 财政年份:
    2011
  • 资助金额:
    $ 65.85万
  • 项目类别:
The mechanism of blood brain barrier impairment in cerebral cavernous malformatio
脑海绵状血管瘤血脑屏障损伤的机制
  • 批准号:
    8320860
  • 财政年份:
    2011
  • 资助金额:
    $ 65.85万
  • 项目类别:
The blood brain barrier in neuroinflammation
神经炎症中的血脑屏障
  • 批准号:
    7781058
  • 财政年份:
    2009
  • 资助金额:
    $ 65.85万
  • 项目类别:
Effect of nicotine on postischemic brain inflammation.
尼古丁对缺血后脑炎症的影响。
  • 批准号:
    7587078
  • 财政年份:
    2008
  • 资助金额:
    $ 65.85万
  • 项目类别:
Blood-Brain Barrier in Neuroinflammation
神经炎症中的血脑屏障
  • 批准号:
    8550172
  • 财政年份:
    2008
  • 资助金额:
    $ 65.85万
  • 项目类别:
Chemokine Effects on Blood-brain Barrier Permeability
趋化因子对血脑屏障通透性的影响
  • 批准号:
    6720934
  • 财政年份:
    2003
  • 资助金额:
    $ 65.85万
  • 项目类别:
Chemokine Effects on Blood-brain Barrier Permeability
趋化因子对血脑屏障通透性的影响
  • 批准号:
    6982792
  • 财政年份:
    2003
  • 资助金额:
    $ 65.85万
  • 项目类别:
Chemokine Effects on Blood-brain Barrier Permeability
趋化因子对血脑屏障通透性的影响
  • 批准号:
    6823224
  • 财政年份:
    2003
  • 资助金额:
    $ 65.85万
  • 项目类别:

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