SUCNR1-driven microglial polarization: Jiawei Xionggui decoction as a therapeutic strategy for Alzheimer's-related neuroinflammation.

Abstract

INTRODUCTION: Succinate receptor 1 (SUCNR1) activation promotes microglial polarization, exacerbating Aβ deposition and neuroinflammation in Alzheimer's disease (AD). While Jiawei Xionggui decoction (JWXG), a traditional Chinese herbal formulation, demonstrates therapeutic potential by modulating microglial activity, its precise molecular mechanisms require further elucidation. OBJECTIVES: To investigate whether JWXG attenuates AD progression by targeting SUCNR1-mediated microglial polarization. METHODS: In vivo, JWXG was administered to APP/PS1 mice with subsequent evaluation of cognitive performance, Aβ deposition, neuroinflammatory markers, and microglial polarization states. Complementary in vitro studies employed Aβ-stimulated BV-2 microglia to examine JWXG's modulation of inflammatory cascades and SUCNR1-dependent polarization. Mechanistic validation was achieved through Sucnr1 knockout (Sucnr1) mice and siRNA-mediated Sucnr1 knockdown in BV-2 cells, both under Aβ challenge conditions, confirming SUCNR1's essential role in mediating JWXG's therapeutic efficacy of AD. RESULTS: JWXG treatment significantly improved cognitive function in APP/PS1 mice, enhancing working memory (Y-maze spontaneous alternation rate) and spatial learning/memory (Morris-water-maze performance), while attenuating neuronal loss and hippocampal degeneration. JWXG administration markedly reduced Aβ burden through enhanced microglial clearance, evidenced by decreased plaque deposition and increased Iba1microglial clustering around deposits. Mechanistically, JWXG suppressed SUCNR1-mediated neuroinflammation by downregulating plaque-associated microglial SUCNR1 expression, inhibiting the succinate-MCT1 (monocarborxylat transporter 1)-SUCNR1 signaling cascade, and shifting microglial polarization from pro-inflammatory (CD86, IL-1β) to anti-inflammatory (CD206, IL-10) phenotypes. Genetic validation using Sucnr1-knockdown models confirmed target specificity, as JWXG's therapeutic effects were significantly attenuated in Sucnr1mice and si-Sucnr1 BV-2 microglia under Aβ exposure conditions. Strong correlations linked SUCNR1 expression with both Aβ burden and microglial polarization markers, establishing SUCNR1-driven microglial polarization as the critical mediator of JWXG's dual anti-neuroinflammatory and neuroprotective effects in Alzheimer's pathogenesis. CONCLUSION: This study provides the first evidence that JWXG mitigates Alzheimer's disease progression by modulating microglial polarization via SUCNR1, as mechanistically validated using Sucnr1gene knockout models. These findings reveal a novel molecular target through which a traditional Chinese medicine formulation may exert anti-neuroinflammatory effects in AD.