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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $1,117,062

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10879542
- **Project number:** 1R01AG083979-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Mervyn Maze
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,117,062
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879542

## Citation

> US National Institutes of Health, RePORTER application 10879542, IL-6 Trans-signaling increases vulnerability to Postoperative Cognitive Decline in Aging and Alzheimers Disease (1R01AG083979-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10879542. Licensed CC0.

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