Xiao-Qun An1, Wei Xi1, Chen-Yun Gu1, Xiao Huang2. 1. MD, Department of Psychiatry, Yangpu District Mental Health Center of Shanghai, 585 Jungong Road, Shanghai (200090), China. 2. MD, Department of Psychological Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai (200032), China.
Abstract
OBJECTIVE: The dysregulation of neuro-inflammation is one of the attributes of the pathogenesis of Alzheimer's disease (AD). Over-expression of complement proteins co-localizes with neurofibrillary tangles, thereby indicating that a complement system may be involved in neuro-inflammation. Here, we report the influence of complement activation on the neuro-inflammation using a microglial cell line. METHODS: first, we performed a cytotoxic assay using the microglial cells BV-2. Second, after treatment of BV-2 cells with Aβ42 and/ or C5a, the anaphylatoxin derived from C5, we determined the expression levels of the pro-inflammatory factors TNF-α, IL-1β, and IL-6. Finally, we explored whether this neuroinflammatory response was mediated by JAK/ STAT3 signaling. RESULTS: C5a had an enhanced effect on the neural cell viability of BV-2 cells treated with Aβ42. In addition, C5a also increased the Aβ-induced neuro-inflammatory response, and these effects were blocked by the C5aR antagonist, PMX205. Finally, we demonstrated that the neuro-inflammatory responses induced by Aβ and C5a were mediated through JAK/STAT3 signaling. By blocking this pathway with an antagonist, AG490, the expression of TNF-α, IL-1β, and IL-6 was alleviated. CONCLUSION: The complement protein C5a could exaggerate the Aβ-induced neuroinflammatory response in microglia, and C5aR may be a potential therapeutic tool for AD treatment.
OBJECTIVE: The dysregulation of neuro-inflammation is one of the attributes of the pathogenesis of Alzheimer's disease (AD). Over-expression of complement proteins co-localizes with neurofibrillary tangles, thereby indicating that a complement system may be involved in neuro-inflammation. Here, we report the influence of complement activation on the neuro-inflammation using a microglial cell line. METHODS: first, we performed a cytotoxic assay using the microglial cells BV-2. Second, after treatment of BV-2 cells with Aβ42 and/ or C5a, the anaphylatoxin derived from C5, we determined the expression levels of the pro-inflammatory factors TNF-α, IL-1β, and IL-6. Finally, we explored whether this neuroinflammatory response was mediated by JAK/ STAT3 signaling. RESULTS:C5a had an enhanced effect on the neural cell viability of BV-2 cells treated with Aβ42. In addition, C5a also increased the Aβ-induced neuro-inflammatory response, and these effects were blocked by the C5aR antagonist, PMX205. Finally, we demonstrated that the neuro-inflammatory responses induced by Aβ and C5a were mediated through JAK/STAT3 signaling. By blocking this pathway with an antagonist, AG490, the expression of TNF-α, IL-1β, and IL-6 was alleviated. CONCLUSION: The complement protein C5a could exaggerate the Aβ-induced neuroinflammatory response in microglia, and C5aR may be a potential therapeutic tool for AD treatment.
Authors: Luis O Soto-Rojas; Mar Pacheco-Herrero; Paola A Martínez-Gómez; B Berenice Campa-Córdoba; Ricardo Apátiga-Pérez; Marcos M Villegas-Rojas; Charles R Harrington; Fidel de la Cruz; Linda Garcés-Ramírez; José Luna-Muñoz Journal: Int J Mol Sci Date: 2021-02-18 Impact factor: 5.923
Authors: Jackson A Roberts; Vijay R Varma; Yang An; Sudhir Varma; Julián Candia; Giovanna Fantoni; Vinod Tiwari; Carlos Anerillas; Andrew Williamson; Atsushi Saito; Tina Loeffler; Irene Schilcher; Ruin Moaddel; Mohammed Khadeer; Jacqueline Lovett; Toshiko Tanaka; Olga Pletnikova; Juan C Troncoso; David A Bennett; Marilyn S Albert; Kaiwen Yu; Mingming Niu; Vahram Haroutunian; Bin Zhang; Junmin Peng; Deborah L Croteau; Susan M Resnick; Myriam Gorospe; Vilhelm A Bohr; Luigi Ferrucci; Madhav Thambisetty Journal: Sci Adv Date: 2021-11-10 Impact factor: 14.957