Licochalcone A Ameliorates Cognitive Dysfunction in an Alzheimer's Disease Model by Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis

Background Endoplasmic reticulum (ER) stress-induced neurodegeneration has been considered an underlying cause of Alzheimer disease (AD). Here, we investigated the beneficial effects of licochalcone A (Lico A), a valuable flavonoid of the root of the Glycyrrhiza species, against cognitive impairment in AD by regulating ER stress.Methods The triple transgenic mouse AD models were used and were administrated 5 or 15 mg/kg Lico A. Cognitive deficits, A beta deposition, ER stress, and neuronal apoptosis were determined using Morris Water Maze test, probe trial, immunofluorescence staining, western blotting, and TUNEL staining. To investigate the mechanisms of how Lico A exerts anti-AD effects, primary hippocampal neurons were isolated from the AD model mice and treated with Lico A, salubrinal, an eIF2 alpha phosphatase inhibitor, ML385, a Nrf2 inhibitor, or LY294002, an inhibitor of PI3K. Pharmacokinetics and toxicity of Lico A (15 mg/kg) in AD mice were evaluated.Results We found that Lico A improved cognitive impairment, decreased A beta plaques, inhibited ER stress, and reduced neuronal apoptosis in the hippocampus and cortex of AD mice. Treatment with Lico A in primary hippocampal neurons exerted the same effects as it did in vivo. Additionally, cotreatment with ML385 or LY294002 significantly impeded the effects of Lico A against ER stress. Moreover, 15 mg/kg Lico A had a good bioavailability and low toxicity in AD mice.Conclusion Our results demonstrated that Lico A ameliorates ER stress-induced neuronal apoptosis by inhibiting PERK/eIF2 alpha/ATF4/CHOP signaling, suggesting the therapeutic potential of Lico A in AD treatment.