Licochalcone E, a β-Amyloid Aggregation Inhibitor, Regulates Microglial M1/M2 Polarization via Inhibition of CTL1-Mediated Choline Uptake

Abstract

Alzheimer’s disease (AD) is thought to be a series of neuroinflammatory diseases caused by abnormal deposits of amyloid-β (Aβ) and tau protein in the brain as part of its etiology. We focused on Aβ aggregation and M1 and M2 microglial polarity in microglia to search for novel therapeutic agents. It has been reported that the inhibition of choline uptake via choline transporter-like protein 1 (CTL1) in microglia preferentially induces M2 microglial polarity. However, the role of the choline transport system on the regulation of microglial M1/M2 polarity in AD is not fully understood. Licochalcones (Licos) A–E, flavonoids extracted from licorice, have been reported to have immunological anti-inflammatory effects, and Lico A inhibits Aβ aggregation. In this study, we compared the efficacy of five Licos, from Lico A to E, at inhibiting Aβ1-42 aggregation. Among the five Licos, Lico E was selected to investigate the relationship between the inhibition of choline uptake and microglial M1/M2 polarization using the immortalized mouse microglial cell line SIM-A9. We newly found that Lico E inhibited choline uptake and Aβ1-42 aggregation in SIM-A9 cells in a concentration-dependent manner, suggesting that the inhibitory effect of Lico E on choline uptake is mediated by CTL1. The mRNA expression of tumor necrosis factor (TNF-α), a marker of M1 microglia, was increased by Aβ1-42, and its effect was inhibited by choline deprivation and Lico E in a concentration-dependent manner. In contrast, the mRNA expression of arginase-1 (Arg-1), a marker of M2 microglia, was increased by IL-4, and its effect was enhanced by choline deprivation and Lico E. We found that Lico E has an inhibitory effect on Aβ aggregation and promotes polarity from M1 to M2 microglia via inhibition of the CTL1 function in microglia. Thus, Lico E may become a leading compound for a novel treatment of AD.

The Role of Licorice Chalcones as Molecular Genes and Signaling Pathways Modulator—A Review of Experimental Implications for Nicotine-Induced Non-Small Cell Lung Cancer Treatment

“…LicoA and LicoB demonstrated anti-Aβ aggregation activity by collapsing the hydrogen bonds inside the Aβ 1–42 protofibril to varying degrees [ 60 ]. LicoE inhibits Aβ 1–42 aggregation through suppression of the choline transporter-like protein 1 function in microglia and TNF-α mRNA expression [ 61 ]. Thus, licos may inhibit excessive accumulation of Aβ in NSCLC cells, leading to the suppression of α7nAChR and its downstream signaling pathways.…”

Licochalcone A: A Potential Multitarget Drug for Alzheimer’s Disease Treatment

“…Furthermore, Muto and colleagues reported that Lico-A inhibits the aggregation of βA1–42, and other licochalcone derivatives also exhibit effectiveness in this process. Specifically, Lico-E demonstrates the ability to inhibit Aβ1–42 aggregation and microglial activation, promoting the activation of neuroprotective microglia M2 [ 56 ]. These findings suggest that Lico-A may hold promise as a potential drug candidate for AD treatment, owing to its ability to disaggregate βA protofibrils.…”

M1 polarization induction by lead and amyloid peptides in microglial cells: Implications for neurodegeneration process

“…These peptides can act as danger signals, stimulating microglial immune responses and fostering the release of pro-inflammatory cytokines, oxidative stress, and neurotoxic mediators. [9][10][11] Heavy metals, including Cd, Zn, and Mn, further exacerbate neuroinflammation by promoting microglial activation, pro-inflammatory cytokine production, and oxidative stress. [12][13][14] The convergence of these factors amplifies the neuroinflammatory cascade, which, when chronically sustained, can inflict significant neuronal damage and ultimately contribute to the pathogenesis of neurodegenerative diseases.…”