IL-6 Trans-signaling increases vulnerability to Postoperative Cognitive Decline in Aging and Alzheimers Disease

Abstract Surgical patients expect to return to their pre-morbid state after the procedure for their underlying condition; unfortunately, perioperative neurocognitive disorders (PNDs) may complicate their recovery resulting in a spectrum of conditions ranging from early-onset delirium to dementia in the longer term. The surgical populations

that are most at risk for developing PNDs are the aged and those with existing cognitive decline, which most often is due to Alzheimer’s Disease (AD). The proportion of surgical patients with these risks is rising steadily. While neuroinflammation plays a pivotal role in the development of PNDs, it remains unknown which

inflammatory cytokines are acting on which cell types to produce the clinical syndrome. Recently, interleukin 6 (IL-6), a pleiotropic cytokine, has come to the fore as a leading candidate for provoking PNDs. Our central hypothesis to be tested, using animal models of aging and AD, is that vulnerability to PNDs is due to an increase

in hippocampal (hc) neuronal IL-6 trans-signaling, which can be assessed perioperatively and can be attenuated with sgp130Fc, a selective blocker. We will test this hypothesis by addressing 5 questions in three Specific Aims (SA). (1) Is the vulnerability to PNDs in aged and AD mouse models associated with upregulation of IL-6 trans-

signaling/neurodegeneration in a part of the brain that contains circuitry involved in memory (SA 1a)? (2) What are the antecedents and/or surrogates of postoperative upregulated IL-6 trans-signaling (SA 1b)? (3) What are the genetic consequences of postoperative IL-6 trans-signaling in hc cells (SA 1c)? (4) Can vulnerability to PNDs

be overcome prophylactically, and therapeutically, with blockade of IL-6 trans-signaling (SA 2)? (5) Is blockade of IL-6 trans-signaling safe for perioperative use (SA 3)? These questions will be answered using validated preclinical mouse models in which aged, AD transgenic, and IL-6 overexpressing mice, with control littermates,

will be subjected to orthopedic surgery, resulting in disrupted spatial memory, and inattentiveness (i.e., ‘cognitive impairment’), that will be assessed with behavioral assays. Levels of the components of IL-6 trans-signaling, blood brain barrier disruption, neurodegeneration, and hc neuronal phosphorylated signal transducer and

activator of transcription (pSTAT3), will be longitudinally assessed perioperatively. The genetic consequences of pSTAT3 upregulation will be assessed by single cell RNA sequencing to establish whether cognate proteins of genes affected by IL-6 trans-signaling can be a therapeutic target. Using sgp130Fc, a selective blocker of IL-

6 trans-signaling, either prophylactically or therapeutically, the effects of blockade on cognitive impairment and IL-6 trans-signaling, as well as its genetic consequences, together with its safety profile, will be investigated. Results from these aims will inform on critically needed therapies for safe prevention and/or reversal of

postoperative cognitive impairments in older adults and subjects with neurodegenerative disorders and possibly for treating delirium and cognitive impairment associated with neuroinflammation in non-surgical settings.