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

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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.