Licorice Compound Glycyrrhizin Reverses Alzheimer's Memory Loss in Aging Mice

Alzheimer's disease (AD) affects tens of millions worldwide, yet disease-modifying treatments remain limited. Neuroinflammation driven by microglial activation is increasingly recognized as a central pathological mechanism, making anti-inflammatory strategies attractive therapeutic targets. Glycyrrhizin (GL), derived from licorice root and widely used in traditional Chinese medicine, has known anti-inflammatory properties, but its direct impact on AD pathology had not been systematically studied.

This study used SAMP8 (P8) mice, a strain that spontaneously develops accelerated aging and exhibits hallmarks of sporadic late-onset AD including memory deficits, amyloid-β accumulation, and tau hyperphosphorylation—more clinically representative than transgenic familial AD models. Forty-week-old P8 mice received either 18β-GL, 18α-GL, or saline for 12 weeks, with age-matched SAMR1 (R1) mice serving as healthy controls (n=6 per group). Cognitive function was assessed via step-through passive avoidance testing. Plasma biomarkers (α-Klotho, IGF-1, 2′,3′-cGAMP, HMGB1, IL-6, TNF-α) were quantified by ELISA, and hippocampal tissue was analyzed by immunohistochemistry for Iba1 (microglia), amyloid-β, and phosphorylated tau.

Untreated P8 mice showed impaired memory retention, significantly reduced plasma α-Klotho and IGF-1, and markedly elevated inflammatory markers compared to R1 controls. Both GL forms significantly restored memory performance in P8 mice, with 18α-GL producing greater latency improvements than 18β-GL. GL administration raised α-Klotho and IGF-1 levels toward those of healthy R1 mice, while substantially reducing 2′,3′-cGAMP and HMGB1—key mediators of the cGAS-STING innate immune pathway implicated in neurodegeneration. Pro-inflammatory cytokines IL-6 and TNF-α were also significantly decreased, with 18α-GL again showing superior efficacy. Hippocampal immunohistochemistry revealed that GL suppressed microglial activation (Iba1), reduced amyloid-β plaque deposition, and lowered phosphorylated tau accumulation—core pathological features of AD.

The mechanistic picture that emerges points to GL inhibiting the HMGB1-cGAS-STING inflammatory axis, thereby dampening microglial activation and downstream cytokine production, which in turn reduces the neurotoxic environment promoting Aβ and tau pathology. The stereoisomer advantage of 18α-GL is consistent with prior reports showing greater anti-inflammatory potency of 18α-glycyrrhetinic acid compared to its 18β counterpart.

These findings position GL, particularly 18α-GL, as a promising multi-target agent for age-related sporadic AD. Caveats include the small sample size (n=6), male-only cohorts, and the translational gap between mouse models and human disease. Human pharmacokinetics and optimal dosing regimens also remain to be established before clinical application.