期刊
FASEB JOURNAL
卷 36, 期 6, 页码 -出版社
WILEY
DOI: 10.1096/fj.202200184RR
关键词
blood-brain barrier; CVN-AD; delirium superimposed on dementia; leucine-rich repeat kinase type 2; microgliosis; mixed lineage kinase type 3; neuroinflammation; URMC-099; vascular cell adhesion molecule type 1
资金
- NIA [R01AG057525]
- NIH [T32 GM135134]
Systemic perturbations following surgical trauma can lead to a neuroimmune cascade, affecting the blood-brain barrier, activating microglia, and contributing to cognitive deficits such as delirium. Delirium superimposed on dementia is a severe complication that increases the vulnerability of the brain to neuroinflammation and neurodegeneration, with molecular mechanisms not yet fully understood. In this study, using a mouse model, the researchers found that the brain-penetrant anti-inflammatory neuroprotective drug URMC-099 could prevent inflammatory endothelial activation, breakdown of the blood-brain barrier, synapse loss, and microglial activation in the delirium superimposed on dementia model.
Systemic perturbations can drive a neuroimmune cascade after surgical trauma, including affecting the blood-brain barrier (BBB), activating microglia, and contributing to cognitive deficits such as delirium. Delirium superimposed on dementia (DSD) is a particularly debilitating complication that renders the brain further vulnerable to neuroinflammation and neurodegeneration, albeit these molecular mechanisms remain poorly understood. Here, we have used an orthopedic model of tibial fracture/fixation in APPSwDI/mNos2(-/-) AD (CVN-AD) mice to investigate relevant pathogenetic mechanisms underlying DSD. We conducted the present study in 6-month-old CVN-AD mice, an age at which we speculated amyloid-beta pathology had not saturated BBB and neuroimmune functioning. We found that URMC-099, our brain-penetrant anti-inflammatory neuroprotective drug, prevented inflammatory endothelial activation, breakdown of the BBB, synapse loss, and microglial activation in our DSD model. Taken together, our data link post-surgical endothelial activation, microglial MafB immunoreactivity, and synapse loss as key substrates for DSD, all of which can be prevented by URMC-099.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据