URMC‐099 prophylaxis prevents hippocampal vascular vulnerability and synaptic damage in an orthopedic model of delirium superimposed on dementia

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‐β 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.