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TGF-β1 blockade of microglial chemotaxis toward Aβ aggregates involves SMAD signaling and down-regulation of CCL5

Wei-Chao Huang1, Feng-Chang Yen2, Feng-Shiun Shie3, Chih-Ming Pan1, Young-Ji Shiao4, Cheng-Ning Yang1, Fong-Lee Huang5, Yen-Jen Sung5* and Huey-Jen Tsay1*

Author Affiliations

1 Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan

2 Division of Psychiatry, Cheng-Hsin Rehabilitation Medical Center, Taipei 11221, Taiwan

3 Division of Mental Health and Substance Abuse, National Health Research Institute, Zhunan 35053, Taiwan

4 National Research Institute of Chinese Medicine, Taipei 11221, Taiwan

5 Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei 11221, Taiwan

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Journal of Neuroinflammation 2010, 7:28  doi:10.1186/1742-2094-7-28

Published: 29 April 2010



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 (Aβ)aggregates. Although transforming growth factor-β1 (TGF-β1) has been shown to down-regulate the expression of chemokines in activated microglia, whether TGF-β1 can reduce the chemotaxis of microglia toward neuritic plaques in AD remains unclear.


In the present study, we investigated the effects of TGF-β1 on Aβ-induced chemotactic migration of BV-2 microglia using time-lapse recording, transwell assay, real-time PCR, ELISA, and western blotting.


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-β1 reduces Aβ-induced BV-2 microglial clustering in a dose-dependent manner. Chemotactic migration of these microglial cells toward Aβ aggregates was significantly attenuated by TGF-β1. However, these microglia remained actively moving without any reduction in migration speed. Pharmacological blockade of TGF-β1 receptor I (ALK5) by SB431542 treatment reduced the inhibitory effects of TGF-β1 on Aβ-induced BV-2 microglial clustering, while preventing TGF-β1-mediated cellular events, including SMAD2 phosphorylation and CCL5 down-regulation.


Our results suggest that TGF-β1 reduces Aβ-induced microglial chemotaxis via the SMAD2 pathway. The down-regulation of CCL5 by TGF-β1 at least partially contributes to the clustering of microglia at Aβ aggregates. The attenuating effects of SB431542 upon TGF-β1-suppressed microglial clustering may be mediated by restoration of CCL5 to normal levels. TGF-β1 may ameliorate microglia-mediated neuroinflammation in AD by preventing activated microglial clustering at neuritic plaques.