초록/요약

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide, accounting for most cases of dementia in elderly individuals, and effective therapies are still lacking. This study was designed to investigate the anti-inflammatory properties of sulforaphane against A beta(1-42) monomers in human THP-1 microglia-like cells. The results showed that sulforaphane preferentially inhibited cathepsin B-and caspase-1-dependent NLRP3 inflammasome activation induced by mostly A beta(1-42) monomers, an effect that potently reduced excessive secretion of the proinflammatory cytokine interleukin-1b (IL-1b). Subsequent mechanistic studies revealed that sulforaphane mitigated the activation of signal transducer and activator of transcription-1 induced by A beta(1-42) monomers. Sulforaphane also increased nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, which was followed by upregulation of heme-oxygenase 1 (HO-1). The anti-inflammatory effect of sulforaphane on A beta(1-42)-induced IL-1b production was diminished by small interfering RNA-mediated knockdown of Nrf2 or HO-1. Moreover, sulforaphane significantly attenuated the levels of microRNA-146a, which is selectively upregulated in the temporal cortex and hippocampus of AD brains. The aforementioned effects of sulforaphane were replicated by the tyrosine kinase inhibitor, herbimycin A, and Nrf2 activator. These results indicate that signal transducer and activator of transcriptione1 dephosphorylation, HO-1 and its upstream effector, Nrf2, play a pivotal role in triggering an anti-inflammatory signaling cascade of sulforaphane that results in decreases of IL-1b release and microRNA-146a production in A beta(1-42)-stimulated human microglia-like cells. These findings suggest that the phytochemical sulforaphane has a potential application in AD therapeutics. (C) 2016 Elsevier Inc. All rights reserved.