Inhibitory effect of a tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal on amyloid-β generation and inflammatory reactions via inhibition of NF-κB and STAT3 activation in cultured astrocytes and microglial BV-2 cells

Abstract

BackgroundAmyloidogenesis is linked to neuroinflammation. The tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal, possesses anti-inflammatory properties in cultured macrophages, and in an arthritis animal model. Because astrocytes and microglia are responsible for amyloidogenesis and inflammatory reactions in the brain, we investigated the anti-inflammatory and anti-amyloidogenic effects of 2,4-bis(p-hydroxyphenyl)-2-butenal in lipopolysaccharide (LPS)-stimulated astrocytes and microglial BV-2 cells.MethodsCultured astrocytes and microglial BV-2 cells were treated with LPS (1 μg/ml) for 24 h, in the presence (1, 2, 5 μM) or absence of 2,4-bis(p-hydroxyphenyl)-2-butenal, and harvested. We performed molecular biological analyses to determine the levels of inflammatory and amyloid-related proteins and molecules, cytokines, Aβ, and secretases activity. Nuclear factor-kappa B (NF-κB) DNA binding activity was determined using gel mobility shift assays.ResultsWe found that 2,4-bis(p-hydroxyphenyl)-2-butenal (1, 2, 5 μM) suppresses the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as the production of nitric oxide (NO), reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in LPS (1 μg/ml)-stimulated astrocytes and microglial BV-2 cells. Further, 2,4-bis(p-hydroxyphenyl)-2-butenal inhibited the transcriptional and DNA binding activity of NF-κB--a transcription factor that regulates genes involved in neuroinflammation and amyloidogenesis via inhibition of IκB degradation as well as nuclear translocation of p50 and p65. Consistent with the inhibitory effect on inflammatory reactions, 2,4-bis(p-hydroxyphenyl)-2-butenal inhibited LPS-elevated Aβ42 levels through attenuation of β- and γ-secretase activities. Moreover, studies using signal transducer and activator of transcription 3 (STAT3) siRNA and a pharmacological inhibitor showed that 2,4-bis(p-hydroxyphenyl)-2-butenal inhibits LPS-induced activation of STAT3.ConclusionsThese results indicate that 2,4-bis(p-hydroxyphenyl)-2-butenal inhibits neuroinflammatory reactions and amyloidogenesis through inhibition of NF-κB and STAT3 activation, and suggest that 2,4-bis(p-hydroxyphenyl)-2-butenal may be useful for the treatment of neuroinflammatory diseases like Alzheimer's disease.

Nuclear Factor-κB Regulates βAPP and β- and γ-Secretases Differently at Physiological and Supraphysiological Aβ Concentrations

“…However, although NF-B-dependent regulation of ␥-secretase has been suggested (43,48,49), the direct regulation of the ␥-secretase components by NF-B has not been detailed. Furthermore, although two NF-B binding sites have been delineated on the ␤APP promoter, no data concern its putative control by NF-B in pathological conditions.…”

Thiacremonone Potentiates Anti-Oxidant Effects to Improve Memory Dysfunction in an APP/PS1 Transgenic Mice Model

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Methanol extracts of Xanthium sibiricum roots inhibit inflammatory responses via the inhibition of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) in murine macrophages

“…5C and D). The iNOS gene promoter contains NF-κB and STAT binding sites in its promoter region, and its expression is regulated by the cooperation between STAT3 and NF-κB (Aktan, 2004;Lee et al, 2011b). Therefore, since MXS inhibited both NF-κB and STAT activation, the levels of iNOS expression can be decreased by MXS.…”