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.

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This 1-year mirror-image analysis with claims-based data demonstrated that RLAI treatment was associated with reductions in relapses and hospital service utilization.

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Sir: Poor compliance with antipsychotic medication, which would potentially lead to disease relapse, has been challenging for psychiatrists when treating schizophrenia.1 Long-acting injection of antipsychotics is an appropriate alternative, since better compliance improves treatment outcomes. Mirror-image studies, in which each patient acts as his/her own control, of long-acting injection of conventional antipsychotics have shown significant decreases in numbers of hospitalizations and days of hospitalization. The development of atypical antipsychotics has provided a new treatment paradigm based on their superior tolerability, if not efficacy. Risperidone long-acting injection (RLAI) is the first licensed long-acting injectable atypical antipsychotic agent and has recently been reported cost-effective by reducing total admission number and inpatient days in a communitybased inpatient setting.3 To our knowledge, a national claimbased database has never been used in any mirror-image study for RLAI.Method. The data source used for this 6-month mirror image study was the Psychiatric Inpatients Medical Claims Data (PIMC) from the National Health Research Institute, Taiwan. The PIMC compiled all the health care utilization records during 1996-2006 for patients who had at least 1 psychiatric hospitalization during 1996-2001. The inclusion criteria required that patients (1) could be observed at least 6 months after the first dose of RLAI, (2) had a primary diagnosis of schizophrenia, and (3) were continuously treated with RLAI for at least 6 months. Patients who received at least 75 mg RLAI total for a 3-month time period were considered continuously treated. The differences in number of acute admissions, hospital days, and emergency room visits between the pre-and post-RLAI periods were compared.Results. A total of 253 from 91,104 patients met the inclusion criteria. As compared to the 6-month pre-RLAI period, the total number of acute admissions was reduced by 35% (136 vs. 88 times, p = .0007), and total hospital stays were reduced by 47% (5856 vs. 3080 days, p = .0002) in the 6-month post-RLAI period. A reduced number of emergency room visits was also observed (80 vs. 67 times) but was not significantly different (p = .24). Since the average hospital stay in acute psychiatric settings was 33 days in Taiwan (data on file; Department of Health, Executive of Yuan, Taiwan; 2007), a secondary analysis to eliminate prolonged hospitalization was conducted by excluding patients who stayed longer than 90 days per admission in the pre-RLAI period. The case number was therefore slightly decreased (N = 237), but the differences in acute admissions (115 vs. 80, p = .0010) and hospital days (3701 vs. 2160 days, p = .0026) remained significant.