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.

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， 暗示白细胞可能导致“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 驱动神经退行性变和脑血管的神经炎症成分 炎。然而，最近的研究表明，与急性发作有关的因素 炎症反应、中性粒细胞会导致病理学和认知障碍 广告。中性粒细胞为何以及如何“侵入”受 AD 影响的大脑并促进持续的 神经退行性疾病仍然很大程度上未知。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以及血管和中性粒细胞的闭塞 导致 AD 炎症过程恶化。我们的初步数据表明 连接粘附分子-A (JAM-A)，一种在炎症中发挥作用的紧密连接分子 作为白细胞粘附分子，在 AD 的脑内皮细胞中表达上调。 JAM-A 的基因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（NET）形成 改善小鼠 AD 的脑血管和实质并减少行为缺陷 模型。因此，该提案强调了 JAM-A 如何驱动中性粒细胞依赖性 AD 中的炎症反应，并特别提出了这样的假设：“JAM-A 在中性粒细胞募集和 NET 形成中发挥关键作用，推动 AD 病症中的炎症和血管损伤”。具体来说，它将评估：a) 全球 JAM-A 敲除如何影响血管和实质中性粒细胞积累 和 AD 中的行为结果，b) 内皮相关 JAM-A 对 AD 中的血管和实质中性粒细胞积聚和行为结果，c) JAM-A 对 AD 产生不利影响的细胞和分子机制和 d) JAM-A 拮抗肽对 AD 诱导的中性粒细胞积累的影响 行为缺陷。总的来说，这些研究将提供与 中性粒细胞积累和 NET 发生的机制不仅与 AD还包括多种疾病状态。希望这将有助于阐明小说 AD 相关炎症的治疗策略。