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

• 批准号: 10752753
• 负责人: ANUSKA V. ANDJELKOVIC-ZOCHOWSKA
• 金额: $ 65.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752753
• 关键词: 3xTg-AD mouse; Acute; Address; Adverse effects; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Anti-Inflammatory Agents; Attenuated; Autoimmune Diseases; Automobile Driving; B-Lymphocytes; Behavioral; Blood; Blood Platelets; Blood Vessels; Brain; CXCL1 gene; Cell Respiration; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular system; Chronic; Cognitive deficits; Complex; Data; Deposition; Development; Disease; Disease Progression; Elements; Encephalitis; Endothelium; Environmental Risk Factor; Event; Extravasation; Foundations; Genes; Genetic; Hemostatic Agents; Immune; Immune response; Impaired cognition; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Invaded; Iron; Knock-out; Knockout Mice; Learning; Leukocyte Adhesion Molecules; Leukocytes; Macrophage; Membrane; Memory; Memory Loss; Microglia; Mitochondria; Modality; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neutrophil Activation; Neutrophil Infiltration; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Peptides; Peripheral; Phenotype; Play; Process; Proteins; Proteomics; Regulation; Role; Senile Plaques; Serum; Side; Synapses; System; TFF1 gene; Testing; Tight Junctions; Transgenic Organisms; Vascular Diseases; antagonist; behavioral outcome; blood vessel occlusion; brain endothelial cell; brain parenchyma; cerebrovascular; cytokine; defined contribution; design; extracellular; genetic manipulation; hyperphosphorylated tau; improved; junctional adhesion molecule; migration; monocyte; mouse model; neurodegenerative dementia; neuroinflammation; neuron loss; neuropathology; neutrophil; novel therapeutic intervention; novel therapeutics; pathogen; peripheral blood; presenilin-1; prevent; recruit; tau Proteins; transcriptomics; treatment strategy; vascular injury

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.

积累的证据表明，阿尔茨海默氏病（AD）相关的炎症 在两个不同但相互关联的隔室中进行：血液和大脑， 暗示白细胞可能导致“大脑激活”，而大脑注射可能 影响炎症介质的外围系统。广告主要是慢性 驱动神经变性和脑血管的神经炎症成分 炎。但是，最近的研究表明涉及急性的因素 炎症反应，中性粒细胞，有助于病理学和认知障碍 广告。为什么以及中性粒细胞如何“侵入”受广告影响的大脑并有助于持续 神经变性仍然在很大程度上未知。拟议的研究旨在阐明 调节脑内皮细胞中性噬相互作用的关键细胞和分子事件 这可能导致血管和中性粒细胞的中性粒细胞募集和阻塞 AD中炎症过程的驱动加剧。我们的初步数据表明 连接粘附分子-A（JAM-A），一种紧密的连接分子，在炎症中 充当白细胞粘附分子，在AD的脑内皮上进行了更新。 JAM-A的基因操纵以及专门设计的JAM-A拮抗剂 肽还原性嗜中性粒细胞浸润和中性粒细胞外陷阱（NET）形成 在脑血管和实质和降低的行为中，在小鼠AD中定义了 模型。因此，该提案突出了JAM-A如何驱动中性粒细胞依赖性 AD中的炎症反应，并特别解决了以下假设：“ JAM-A-A 在中性粒细胞招募中起关键作用，净形成驱动 在广告条件下炎症和血管损伤”。具体而言，它将评估：a） 全球JAM-A敲除如何影响血管和副粒细胞积累 和AD中的行为结果，b）内皮相关的JAM-A对 AD中的血管和副伴嗜中性粒细胞的积累和行为结果，c） JAM-A在AD和D中的不良反应的基础的细胞和分子机制） JAM-A-A拮抗剂肽对AD诱导的中性粒细胞积累和 行为定义。这些研究共同提供了与 中性粒细胞积累的机制和发生的网不仅与 广告，也适用于多种疾病状态。希望这将有助于阐明小说 治疗AD相关炎症的治疗策略。