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

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Abstract
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, Aβ 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 eIF2α 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 Aβ 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/eIF2α/ATF4/CHOP signaling, suggesting the therapeutic potential of Lico A in AD treatment.
Funding Information
  • General Project of National Natural Science Foundation of China (81774021, 82074504)
  • Construction project of high-level key disciplines of traditional Chinese medicine in National Administration of Traditional Chinese Medicine (Chinese Medicine People’s Education Letter No. 85 [2023])

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