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BackgroundMer tyrosine kinase (MerTK) activity necessary for amyloid-stimulated phagocytosis strongly implicates that MerTK dysregulation might contribute to chronic inflammation implicated in Alzheimer’s disease (AD) pathology. However, the precise mechanism involved in the regulation of MerTK expression by amyloid-β (Aβ) in proinflammatory environment has not yet been ascertained.MethodsThe objective of this study was to determine the underlying mechanism involved in Aβ-mediated decrease in MerTK expression through Aβ-mediated regulation of MerTK expression and its modulation by sulforaphane in human THP-1 macrophages challenged with Aβ1-42. We used protein preparation, Ca2+ influx fluorescence imaging, nuclear fractionation, Western blotting techniques, and small interfering RNA (siRNA) knockdown to perform our study.ResultsAβ1-42 elicited a marked decrease in MerTK expression along with increased intracellular Ca2+ level and induction of proinflammatory cytokines such as IL-1β and TNF-α. Ionomycin A and thapsigargin also increased intracellular Ca2+ levels and production of IL-1β and TNF-α, mimicking the effect of Aβ1-42. In contrast, the Aβ1-42-evoked responses were attenuated by depletion of Ca2+ with ethylene glycol tetraacetic acid. Furthermore, recombinant IL-1β or TNF-α elicited a decrease in MerTK expression. However, immunodepletion of IL-1β or TNF-α with neutralizing antibodies significantly inhibited Aβ1-42-mediated downregulation of MerTK expression. Notably, sulforaphane treatment potently inhibited Aβ1-42-induced intracellular Ca2+ level and rescued the decrease in MerTK expression by blocking nuclear factor-κB (NF-κB) nuclear translocation, thereby decreasing IL-1β and TNF-α production upon Aβ1-42 stimulation. Such adverse effects of sulforaphane were replicated by BAY 11-7082, a NF-κB inhibitor. Moreover, sulforaphane’s anti-inflammatory effects on Aβ1-42-induced production of IL-1β and TNF-α were significantly diminished by siRNA-mediated knockdown of MerTK, confirming a critical role of MerTK in suppressing Aβ1-42-induced innate immune response.ConclusionThese findings implicate that targeting of MerTK with phytochemical sulforaphane as a mechanism for preventing Aβ1-42-induced neuroinflammation has potential to be applied in AD therapeutics.

The objective of this study was to investigate the effect of resveratrol (a natural polyphenolic phytostilbene) on tau hyperphosphorylation and oxidative damage induced by sodium orthovanadate (NaVO), the prevalent species of vanadium (vanadate), in rat hippocampal slices. Our results showed that resveratrol significantly inhibited NaVO-induced hyperphosphorylation of tau at the Ser396 (p-S396-tau) site, which is upregulated in the hippocampus of Alzheimer's disease (AD) brains and principally linked to AD-associated cognitive dysfunction. Subsequent mechanistic studies revealed that reduction of ERK1/2 activation was involved in the inhibitory effect of resveratrol by inhibiting the ERK1/2 pathway with SL327 mimicking the aforementioned effect of resveratrol. Moreover, resveratrol potently induced GSK-3β Ser9 phosphorylation and reduced NaVO-induced p-S396-tau levels, which were markedly replicated by pharmacologic inhibition of GSK-3β with LiCl. These results indicate that resveratrol could suppress NaVO-induced p-S396-tau levels via downregulating ERK1/2 and GSK-3β signaling cascades in rat hippocampal slices. In addition, resveratrol diminished the increased extracellular reactive oxygen species generation and hippocampal toxicity upon long-term exposure to NaVO or FeCl. Our findings strongly support the notion that resveratrol may serve as a potential nutraceutical agent for AD.

The S100A9 protein is an important proinflammatory factor of innate immunity that has been proposed to participate in inflammation associated with the pathogenesis of Alzheimer's disease. Here, we provide insights into the potential roles of extracellular S100A9 in the interaction with the immune response in human THP-1 monocytic cells that have been challenged with amyloid β1-42 (Aβ1-42) monomers instead of oligomers. Extracellular S100A9 alone produced a stimulatory effect on tumor necrosis factor-α and interleukin-1β, expression as well as released monocyte chemoattractant protein-1 into culture supernatants, which was accompanied by an increased level of matrix metalloproteinas-9 activity. Importantly, co-stimulation with S100A9 and Aβ1-42 resulted in a marked enhancement of Aβ1-42-mediated release of these proinflammatory mediators under the same experimental conditions, whereas heat inactivated S100A9 had little effect. Our findings clearly suggest that excess S100A9 protein may play an important role in the pathological processes of Alzheimer's disease by exacerbating the Aβ1-42-induced innate immune response.