Tetrahydroxy stilbene glycoside ameliorates neuroinflammation for Alzheimer's disease via cGAS-STING

Jun 16, 2023European journal of pharmacology

Tetrahydroxy stilbene glycoside may reduce brain inflammation in Alzheimer's disease through the cGAS-STING pathway

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Abstract

Alzheimer's disease transgenic mice showed cognitive deficits alongside elevated serum and brain inflammation.

Cognitive improvement in AD mice was observed after treatment with tetrahydroxy stilbene glucoside (TSG) from Polygonum multiflorum.
TSG treatment resulted in reduced levels of inflammatory cytokines in the serum and suppressed microglial activation in the brain.
The decrease in inflammation may be linked to a reduction in the cGAS-STING immune response and NLRP3 inflammasome activation.
In cell culture, TSG reversed the activation of M1-type microglia and normalized the cGAS-STING pathway.
TSG also inhibited the production of various inflammatory cytokines and regulatory proteins involved in inflammatory responses.

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Alzheimer's disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear. In this study, we demonstrated that AD transgenic mice exhibited cognitive deficits accompanied by the elevated serum and brain inflammation. Treating with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) from the Chinese herb Polygonum multiflorum that has been well known for its unique anti-aging effect, learning-memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN-γ induced microglia activation showed that TSG reversed the polarization status of M1-type microglia to restore the quiescence, and cGAS-STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL-1β, IL-6, TNF-α, IFN-α and IFN-β, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN-γ-stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS-STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS-STING inhibitors. Taken together, our findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS-STING signaling pathway in AD.

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Tetrahydroxy stilbene glycoside ameliorates neuroinflammation for Alzheimer's disease via cGAS-STING

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