國家衛生研究院 NHRI:Item 3990099045/4912
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    题名: TGF-beta 1 blockade of microglial chemotaxis toward A beta aggregates involves SMAD signaling and down-regulation of CCL5
    作者: Huang, WC;Yen, FC;Shie, FS;Pan, CM;Shiao, YJ;Yang, CN;Huang, FL;Sung, YJ;Tsay, HJ
    贡献者: Division of Mental Health and Addiction Medicine
    摘要: Background: Overactivated microglia that cluster at neuritic plaques constantly release neurotoxins, which actively contribute to progressive neurodegeneration in Alzheimer's disease (AD). Therefore, attenuating microglial clustering can reduce focal neuroinflammation at neuritic plaques. Previously, we identified CCL5 and CCL2 as prominent chemokines that mediate the chemotaxis of microglia toward beta-amyloid (A beta) aggregates. Although transforming growth factor-beta 1 (TGF-beta 1) has been shown to down-regulate the expression of chemokines in activated microglia, whether TGF-beta 1 can reduce the chemotaxis of microglia toward neuritic plaques in AD remains unclear. Methods: In the present study, we investigated the effects of TGF-beta 1 on A beta-induced chemotactic migration of BV-2 microglia using time-lapse recording, transwell assay, real-time PCR, ELISA, and western blotting. Results: The cell tracing results suggest that the morphological characteristics and migratory patterns of BV-2 microglia resemble those of microglia in slice cultures. Using this model system, we discovered that TGF-beta 1 reduces A beta-induced BV-2 microglial clustering in a dose-dependent manner. Chemotactic migration of these microglial cells toward A beta aggregates was significantly attenuated by TGF-beta 1. However, these microglia remained actively moving without any reduction in migration speed. Pharmacological blockade of TGF-beta 1 receptor I (ALK5) by SB431542 treatment reduced the inhibitory effects of TGF-beta 1 on A beta- induced BV- 2 microglial clustering, while preventing TGF-beta 1-mediated cellular events, including SMAD2 phosphorylation and CCL5 down-regulation. Conclusions: Our results suggest that TGF-beta 1 reduces A beta-induced microglial chemotaxis via the SMAD2 pathway. The down-regulation of CCL5 by TGF-beta 1 at least partially contributes to the clustering of microglia at A beta aggregates. The attenuating effects of SB431542 upon TGF-beta 1-suppressed microglial clustering may be mediated by restoration of CCL5 to normal levels. TGF-beta 1 may ameliorate microglia-mediated neuroinflammation in AD by preventing activated microglial clustering at neuritic plaques.
    日期: 2010-04
    關聯: Journal of Neuroinflammation. 2010 Apr;7:Article number 28.
    Link to: http://dx.doi.org/10.1186/1742-2094-7-28
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1742-2094&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000278293500001
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=77951617994
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