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

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. This work was supported by the Natural Science Foundation of Guangxi Zhuang Autonomous Region (No. 2020GXNSFDA238009), Guangxi Science and Technology Program (No.

GKLT2600640012), and Guangxi Zhuang Autonomous Region Health Commission Research Project (Nos. Z-C20230870 and GXZYC20240403). These authors contributed equally: Muyan Ma, Fang Shi.

Laboratory of Neuroscience, The first Affiliated Hospital of Guilin Medical University, Guilin, China Guangxi Clinical Research Center for Neurological Diseases, The first Affiliated Hospital of Guilin Medical University, Guilin, China Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China The authors declare no competing interests. The animal experiments of the project met the requirements of animal welfare ethics and passed the animal welfare ethics investigation by IACUC of Guilin Medical University. Investigation Number:GLMC-IACUC-20241041.