licochalcone-a and Alzheimer-Disease

Licochalcone A (Lico-A) is a flavonoid compound derived from the root of the Glycyrrhiza species, a plant commonly used in traditional Chinese medicine. While the Glycyrrhiza species has shown promise in treating various diseases such as cancer, obesity, and skin diseases due to its active compounds, the investigation of Licochalcone A's effects on the central nervous system and its potential application in Alzheimer's disease (AD) treatment have garnered significant interest. Studies have reported the neuroprotective effects of Lico-A, suggesting its potential as a multitarget compound. Lico-A acts as a PTP1B inhibitor, enhancing cognitive activity through the BDNF-TrkB pathway and exhibiting inhibitory effects on microglia activation, which enables mitigation of neuroinflammation. Moreover, Lico-A inhibits c-Jun N-terminal kinase 1, a key enzyme involved in tau phosphorylation, and modulates the brain insulin receptor, which plays a role in cognitive processes. Lico-A also acts as an acetylcholinesterase inhibitor, leading to increased levels of the neurotransmitter acetylcholine (Ach) in the brain. This mechanism enhances cognitive capacity in individuals with AD. Finally, Lico-A has shown the ability to reduce amyloid plaques, a hallmark of AD, and exhibits antioxidant properties by activating the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defense mechanisms. In the present review, we discuss the available findings analyzing the potential of Lico-A as a neuroprotective agent. Continued research on Lico-A holds promise for the development of novel treatments for cognitive disorders and neurodegenerative diseases, including AD. Further investigations into its multitarget action and elucidation of underlying mechanisms will contribute to our understanding of its therapeutic potential.

Topics: Acetylcholinesterase; Alzheimer Disease; Antioxidants; Chalcones; Humans

Amyloid-beta (Aβ) protofibrils are closely related to Alzheimer's disease. Their behaviors with or without the presence of Aβ fibrillization inhibitors have been intensively studied by molecular dynamics simulations. In this work, the molecular mechanisms of licochalcone A and licochalcone B on destabilizing Aβ(1-42) protofibrils are explored. It is found that both two licochalcones can disorder the configuration of the Aβ(1-42) protofibril. The stable interactions between the Aβ(1-42) protofibril and licochalcone A or licochalcone B are able to be formed. A reduction of the β-sheet structure contents and an increment of the random coil structures of Aβ(1-42) protofibril are observed in the presence of either licochalcone A or licochalcone B. The hydrogen bonds inside the Aβ(1-42) protofibril could be partially collapsed to varying degrees by two licochalcones. Furthermore, the van der Waals interactions between Aβ(1-42) protofibril and licochalcone A make an important contribution to the binding free energy, while the contribution of the electrostatic interactions between Aβ(1-42) protofibril and licochalcone B is more prominent in the binding affinity. Our work may help in the development of new drug candidates for disrupting the Aβ protofibril.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Humans; Molecular Dynamics Simulation; Peptide Fragments; Protein Binding