Ginsenoside Re mitigates Aβ1-42-induced neurotoxicity by promoting autophagy and suppressing NLRP3 inflammasome

Le résumé fourni par la source

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and neuroinflammation. Activation of NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome in microglia significantly contributes to AD-associated neuroinflammation and neuronal damage. Ginsenoside Re (G-Re), a major bioactive constituent of Panax ginseng , exhibits anti-inflammatory properties, but its role in modulating inflammasome activation in AD remains unclear. This study evaluated the therapeutic potential of G-Re in mice intracerebroventricularly injected with Aβ 1-42 and delineated its molecular mechanisms in complementary cell-based models. We employed behavioral testing, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assays, Annexin V apoptosis assays, and mitochondrial functional assays. Intraperitoneal administration of G-Re significantly improved cognitive performance, as evidenced by enhanced outcomes in the T-maze and novel object recognition tests. G-Re treatment reduced microglial activation and interleukin-1β (IL-1β) levels in the cortex and hippocampus. In vitro, G-Re protected neurons from conditioned medium derived from Aβ 1-42 -stimulated microglia, showing neuroprotection comparable to anti-IL-1β treatment. G-Re also inhibited Aβ 1-42 -induced activation of the NLRP3 inflammasome, as indicated by diminished levels of NLRP3, cleaved caspase-1, cleaved gasdermin D (GSDMD), IL-1β, and IL-18 in brain tissues and cultured microglia. Mechanistically, G-Re reduced mitochondrial reactive oxygen species (mtROS), preserved mitochondrial membrane potential, and activated autophagy via SIRT1/AMPK/mTOR signaling, thereby suppressing inflammasome activation. G-Re ameliorates Aβ 1-42 -induced neuroinflammation and cognitive impairment by restoring mitochondrial homeostasis, enhancing autophagy, and suppressing NLRP3 inflammasome activation. These findings suggest G-Re as a potential therapeutic intervention for neurodegenerative disorders including AD.

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