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