Abstract
BackgroundOveractivated 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.MethodsIn 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.ResultsThe 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.ConclusionsOur 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.
Highlights
Overactivated microglia that cluster at neuritic plaques constantly release neurotoxins, which actively contribute to progressive neurodegeneration in Alzheimer's disease (AD)
Our results suggest that transforming growth factor-β1 (TGF-β1) reduces Aβ-induced microglial chemotaxis via the SMAD2 pathway
Our results indicate that TGF-β1 dramatically diminishes clustering of BV-2 microglia at aggregated Aβ25-35 (Fig. 1A)
Summary
Overactivated microglia that cluster at neuritic plaques constantly release neurotoxins, which actively contribute to progressive neurodegeneration in Alzheimer's disease (AD). We identified CCL5 as a prominent chemokine that mediates Aβ-induced clustering of BV-2 microglia [13] These results suggest that chemokines actively participate in microglial chemotaxis toward neuritic plaques and that elevated chemokine levels can recruit more microglia toward these plaques. The regulatory role of TGF-β1 in AD pathogenesis, has been intensively examined by overexpressing TGF-β1 or blocking the TGF-β-SMAD signaling pathway [14,18,19] Wyss-Coray et al showed that overexpression of TGF-β1 prominently reduces plaque formation and Aβ accumulation in hAPP mice [19] Their data suggest that TGF-β1 enhances Aβ clearance by BV-2 microglia, and, the TGF-β1 pathway may serve as a potential therapeutic target for AD [20]. The role of TGF-β1-SMAD signaling in AD pathogenesis warrants further investigation
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