In amyloid-β (Aβ)-stimulated microglial cells, blockade of chloride intracellular ion channel 1 (CLIC1) reverts the increase in tumor necrosis factor-α and nitric oxide (NO) production and results in neuroprotection of cocultured neurons. This effect could be of therapeutic efficacy in Alzheimer's disease (AD), where microglial activation may contribute to neurodegeneration, but it could reduce Aβ phagocytosis, which could facilitate amyloid plaque removal. Here, we analyzed the CLIC1 blockade effect on Aβ-stimulated mononuclear phagocytosis. In the microglial cell line BV-2, Aβ25-35 treatment enhanced fluorescent bead phagocytosis, which persisted also in the presence of IAA-94, a CLIC1 channel blocker. The same result was obtained in rat primary microglia and in BV2 cells, where CLIC1 expression had been knocked down with a plasmid producing small interfering RNAs. To address specifically the issue of Aβ phagocytosis, we treated BV-2 cells with biotinylated Aβ1-42 and measured intracellular amyloid by morphometric analysis. IAA-94-treated cells showed an increased Aβ phagocytosis after 24 hr and efficient degradation of ingested material after 72 hr. In addition, we tested Aβ1-42 phagocytosis in adult rat peritoneal macrophages. Also, these cells actively phagocytosed Aβ1-42 in the presence of IAA-94. However, the increased expression of inducible NO synthase (iNOS), stimulated by Aβ, was reverted by IAA-94. In parallel, a decrease in NO release was detected. These results suggest that blockade of CLIC1 stimulates Aβ phagocytosis in mononuclear phagocytes while inhibiting the induction of iNOS and further point to CLIC1 as a possible therapeutic target in AD.
|Titolo:||Blockade of chloride intracellular ion channel 1 stimulates Abeta phagocytosis|
MAZZANTI, MICHELE (Penultimo)
|Parole Chiave:||Alzheimer's disease; Amyloid-b; Chloride intracellular ion channel 1; Microglia; Phagocytosis|
|Settore Scientifico Disciplinare:||Settore BIO/09 - Fisiologia|
|Data di pubblicazione:||15-ago-2008|
|Digital Object Identifier (DOI):||10.1002/jnr.21693|
|Appare nelle tipologie:||01 - Articolo su periodico|