IL-6 trans-signaling suppresses amyloid-β production through an ADAM17-dependent positive feedback loop in Alzheimer’s disease

Abstract Alzheimer’s disease (AD) represents a major neurodegenerative threat, with elevated Interleukin-6 (IL-6) levels increasingly recognized as a key player in its pathology. However, the mechanistic links between IL-6 signaling and AD progression remain largely elusive. To address this gap, we employed an integrated approach combining bioinformatics, molecular biology, and preclinical models to dissect IL-6’s multifaceted role in AD pathogenesis. Protein-protein interaction (PPI) network analysis identified IL-6 and its receptor (IL-6R) as key hub genes. Experimental validation in SHSY5Y-APP cellular AD models confirmed significant upregulation of IL-6, IL-6R, and soluble IL-6R(sIL-6R) compared to control groups, validating our bioinformatics predictions. Moreover, our results reveal a striking dichotomy in IL-6 signaling: classical signaling activation promotes Aβ production, while trans-signaling exerts inhibitory effects. This trans-signaling mechanism mediates the upregulation of ADAM17 expression through JAK/STAT3 pathway activation. Notably, treatment with TAPI-1, a specific ADAM17 inhibitor, abolished both the ADAM17 upregulation and the associated Aβ reduction, confirming the pathway’s specificity. In vivo studies in APP/PS1 transgenic mice further demonstrated that trans-signaling activation not only restored spatial memory deficits but also attenuated hippocampal Aβ deposition. Collectively, this work indicates a novel positive feedback loop between IL-6 trans-signaling and ADAM17 that suppresses Aβ accumulation in AD pathology. These results highlight the therapeutic potential of targeting IL-6 trans-signaling pathways to mitigate pathological Aβ accumulation.