Understanding the role of senescence on post-operative neuroinflammation

Abstract Peripheral tissue injury, which arises due to surgical trauma, can negatively impact brain function, particularly in older and/or frail patients that may already suffer from neurodegeneration and Alzheimer’s disease (AD). The blood-brain barrier (BBB) represents a key interface between the periphery and the brain with important roles in regulating neuroimmune interactions. Dysfunction of the BBB has been reported in many neurologic conditions, including AD and Alzheimer’s Disease Related Dementias (ADRD). BBB dysfunction during normal aging can also contribute to neuroinflammation and cognitive loss via altered transcellular permeability, trafficking of blood- derived factors in the brain parenchyma. BBB dysfunction and neuroinflammation are growing significant interest in postoperative complications such as delirium. Indeed, delirium is a form of ADRD that is associated with worse outcomes both in patients with and without neurodegeneration, and is especially common following major surgery such as orthopedic procedures. In this research, we will address why the aging brain is more susceptible to postoperative delirium and neuroinflammation by using a clinically relevant orthopedic fracture model in mice that displays various cardinal features of BBB impairment, glial dysfunction, and cellular senescence. Our central hypothesis is that senescent cell burden in aged individuals exacerbates systemic inflammation, hastens BBB breaching, and promotes neuroinflammation leading to delirium. We will test this hypothesis by combining a transgenic mouse model and pharmacological drug-mediated elimination of senescent cells. The latter will also lead to the validation of a clinically applicable therapeutic formulation/regimen to treat post-operative neuroinflammation and delirium with drugs (senolytics) currently tested in humans for other disorders, including AD. We have 3 objectives: 1) determine the role of senescent cells on systemic inflammation, BBB breaching, and neuroinflammation following surgical trauma, 2) examine the efficacy of senolytic drug, D/Q-mediated senescent cell clearance in preventing neuroinflammation, and 3) determine the reciprocal interactions between the blood-borne factors and the BBB using a microphysiological system. Together the studies will provide new insights into the effects of peripheral surgical trauma on the blood-brain interface, neuroinflammation, and cognitive impairments such as delirium. This is a highly significant step toward identifying pharmacologic targets to prevent delirium and improve outcomes after surgery in elderly patients.