Glycyrrhizin Ameliorates Learning and Memory Impairment via Inhibition of Neuroinflammation in an Alzheimer’s Disease Mouse Model SAMP8

Neuroinflammation plays a central role in Alzheimer’s disease (AD). Glycyrrhizin (GL), a major component of licorice, exhibits anti-inflammatory effects, but its effects on AD pathology remain unclear. To investigate the effects of GL (18β-glycyrrhizin, 18β-GL) and its stereoisomer (18α-glycyrrhizin, 18α-GL) on cognitive function, neuroinflammation, and AD pathology in senescence-accelerated mouse prone 8 (SAMP8; P8) mice, 40-week-old P8 male mice, an AD model due to aging, and the control (senescence-accelerated mouse resistant 1, SAMR1; R1) mice were treated with 18β-GL, 18α-GL and physiological saline (control) for 12 weeks (n = 6 in each group). Cognitive function was evaluated using a step-through passive avoidance test. Plasma levels of α-Klotho, IGF-1, 2′,3′-cyclic GMP-AMP (2′,3′-cGAMP), HMGB1, IL-6, and TNF-α were measured by ELISA. Hippocampal microglial activation (Iba1), amyloid-β (Aβ) deposition, and phosphorylated tau (p-Tau) were assessed by immunohistochemistry. Aged P8 mice showed impaired memory, decreased α-Klotho and IGF-1 levels, and increased inflammatory markers compared with R1 mice. GL significantly improved memory performance, reduced inflammatory markers, and suppressed Iba1 activation, as well as Aβ and p-Tau accumulation. These effects were associated with inhibition of the cGAS–STING pathway, as indicated by reduced 2′,3′-cGAMP and HMGB1 levels. GL ameliorates AD pathology by inhibiting neuroinflammation, suggesting its therapeutic potential for AD.