Role of pericytes in postoperative neurocognitive disorder during aging

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ABSTRACT Perioperative neurocognitive disorders (PNDs) include acute delirium and long-lasting cognitive decline. These complications have become highly prevalent in our geriatric population, especially following common surgical procedures such as orthopedic fracture repairs. Delirium impacts over 50% of older adults after orthopedic surgery, which is often performed in frail patients including those with pre-existing dementia. Delirium and dementia have bidirectional relationships even though they have distinct pathophysiologies. To-date it remains unknown how a transient episode of delirium can contribute to the development of Alzheimer’s Disease and related dementia (ADRD). We have established and validated a clinically relevant mouse model to study the acute impact of surgery on delirium-like pathology in rodents. With this model we found significant changes in blood-brain barrier (BBB) function and neuroinflammatory markers. Our Preliminary Results indicate that surgery induces vascular dysfunction in the central nervous system (CNS), with a rapid loss of ~58% of pericytes in the hippocampal microvasculature. Pericytes in the CNS play key roles in neurovascular integrity and supporting communication and signaling with other cell types. Recent studies from Alzheimer’s disease (AD) samples demonstrated that pericyte dysfunction can promote neurodegeneration. The role of pericytes in delirium and their putative contribution to long-lasting cognitive decline and ADRD remain unknown This proposal will begin to investigate whether protracted loss of pericytes after surgery in aged mice predisposes to long-term cognitive decline and neurodegeneration. The Objective is to define the role of pericytes in postoperative neurocognitive disorders. Our Central Hypothesis is that aging prolongs pericytes dysfunction after surgery leading to enduring neurovascular disorders and dementia. The hypothesis will be tested in 2 aims: 1) Identify the effects of surgery- induced pericyte loss on acute and long-term neuroinflammation and neuronal loss; and 2) Determine the role of pericytes in postoperative neurocognitive disorder. We will subject adult (3-months) and aged (18-mo-old) male and female mice to orthopedic surgery, and evaluate changes in pericytes, neuronal loss, and neurodegenerative markers at 24 hr and 3 months after surgery. We will also treat aged mice with PDGF-BB to boost PDGFRb signaling and promote pericytes recruitment to possibly prevent long-lasting cognitive pathology sequalae, focusing on PNDs behaviors and neurodegenerative biomarkers 3 months after surgery. Overall, results from this project will provide a foundation to identify novel and specific targets to prevent PNDs and curtail the effects of surgery on vulnerable older adults with AD or other forms of dementia and neurodegeneration.