Glycyrrhiza glabra exhibits disease-modifying effects in Alzheimer's disease through restoration of mitochondrial function, synaptic plasticity, and kinase signaling.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and neuronal dysfunction. Current therapeutic treatments are limited to symptomatic relief and often cause significant adverse effects, underscoring the need for alternative medicinal approaches with potent neuroprotective efficacy and minimal side effects. Glycyrrhiza glabra, rich in major bioactive constituents such as Glycyrrhizic acid, glabridin, liquiritin, rhamnoliquirilin, liquiritigenin, and prenyllicoflavone A, has been historically used in Ayurveda and exhibits therapeutic potential; however, its efficacy in mitigating AD-associated pathological conditions remains poorly understood. METHODS: This study investigates the neuroprotective properties of G. glabra root extract in Aβ42-treated human neuroblastoma (IMR-32) cells and Aβ42-overexpressing Drosophila melanogaster transgenic flies. Various behavioral and molecular biology techniques were employed, including immunofluorescence, qRT-PCR, flow cytometry, and western blotting, to investigate the effects of G. glabra root extract. RESULTS: Our results demonstrated that Aβ42 treatment induced aberrant alterations in several proteins associated with Alzheimer's pathology, mitochondrial dysfunction, cell-cycle re-entry, and synaptic activity. Co-treatment with G. glabra extract restored these protein levels and mitigated Aβ42-induced hyperactivation of key signaling pathways. Furthermore, G. glabra attenuated Aβ42-induced apoptotic signaling, modulating pro- and anti-apoptotic protein expression profiles in both in vitro and in vivo models. CONCLUSION: Our findings indicate that G. glabra treatment restores the expression of key proteins altered in AD pathology, suggesting a potential neuroprotective mechanism mediated through the regulation of the MEK/ERK-1/2, PI3K/AKT/GSK3β, and CDK5/p35/p25 pathways. This study provides a molecular rationale for the historical use of G. glabra, demonstrating its ability to rescue altered AD-associated protein markers in both cellular and Drosophila models. While further research is necessary to fully elucidate the neuroprotective mechanisms of G. glabra, these findings pave the way for downstream validation of the extract as a promising natural therapeutic candidate for Alzheimer's disease.