Overview Aging and neurodegenerative diseases are projected to steadily rise; individuals with these characteristics and conditions are more likely to require surgical interventions and are particularly vulnerable for the development of Perioperative Neurocognitive Disorders (PNDs). Currently, there are no therapies that can mitigate PNDs which results in decreased quality of life, higher mortality and is estimated to incur annual US healthcare costs in the 1st year after diagnosis of ~ $33 billion. While we had shown that neuroinflammation plays a pivotal role in the development of PNDs, it remained unknown which inflammatory cytokines act on which cell types to produce the clinical syndrome. Our recent studies suggest that the pleiotropic cytokine interleukin 6 (IL-6), acting through a trans-signaling mechanism on hippocampal neurons, plays a crucial for the development of PNDs in an animal model. We posit that the vulnerability to PNDs in the setting of aging and neurodegenerative diseases, is due to an increase in hippocampal neuronal IL-6 trans-signaling. Using validated preclinical mouse models in which different strains of aged mice, Alzheimer Disease (AD) transgenics, and IL-6 overexpressing mice, are subjected to orthopedic surgery thats disrupts spatial memory and inattentiveness, we will address the following questions. (1) Is the vulnerability to PNDs in aged and AD mouse models dependent on upregulation of IL-6 trans-signaling in a part of the brain that contains circuitry involved in memory? (2) What are the antecedents and/or surrogates of postoperative upregulated IL-6 trans-signaling? (3) What are the genetic consequences of postoperative IL-6 trans-signaling in cells of the hippocampus with impaired long-term potentiation? (4) Can vulnerability to PNDs be overcome prophylactically, and therapeutically, with blockade of IL-6 trans-signaling? (5) Is blockade of IL-6 trans-signaling safe for perioperative use? Affiliated Lab Center for Cerebrovascular Research Principal investigator UCSF Mervyn Maze, MB, CHB Professor Collaborators UCSF Hua Su, MD Professor Zhonghui Guan, MD Professor Arun Prakash Budde, MD, PhD Professor External persons Niccolo Terrando PhD, Associate Professor, Duke University Seeking collaborators We are interested to collaborate with investigators that use brain imaging techniques and electrophysiology to detect upregulated IL-6 trans-signaling in different brain regions. Email Us Support this research We are interested in developing ties with groups/foundations that advocate on behalf of the aging population and for patients with neurodegenerative conditions that result in cognitive decline. Support
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