Interleukin17A Promotes Postoperative Cognitive Dysfunction by Triggering [beta]-Amyloid Accumulation via the Transforming Growth Factor-[beta] (TGF[beta])/Smad Signaling Pathway

• Published in: PloS one 2015-10, Vol.10 (10)
• Main Authors: Tian, Ayong, Ma, Hong, Zhang, Rongwei, Tan, Wenfei, Wang, Xiaolong, Wu, Binyang, Wang, Jun, Wan, Chengfu
• Format: Article
• Language: English
• Subjects: Cellular signal transduction; Cognitive disorders; Development and progression; Genetic aspects; Health aspects; Immune response; Interleukins; Postoperative period
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0141596

Although postoperative cognitive dysfunction (POCD) is relatively common in elderly patients who have undergone major surgery, the mechanisms underlying this postoperative complication are unclear. Previously, we have investigated the role of cytokine-mediated hippocampal inflammation in the development of POCD in a rat model. Here, we sought to determine in mice the role of cytokine interleukin17A (IL17A) in POCD and to characterize the associated signaling pathways. Old mice underwent hepatectomy surgery in the presence or absence of IL17A monoclonal antibody, and cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimer's disease (AD) were assessed. We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, [beta]-amyloid.sub.1-42 (A[beta].sub.1-42) production, upregulation of transforming growth factor-[beta] (TGF[beta]), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus. Surgery-induced changes in cognitive dysfunction and changes in A[beta].sub.1-42 and TGF[beta]/Smad signaling were prevented by the administration of IL17A monoclonal antibody. In addition, IL17A-stimulated TGF[beta]/Smad activation and A[beta].sub.1-42 expression were reversed by IL17A receptor small interfering RNA and a TGF[beta] receptor inhibitor in cultured astrocytes. Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGF[beta]/Smad pathway dependent A[beta].sub.1-42 accumulation in old subjects. These changes likely contribute to the cognitive decline seen in POCD.