The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway

Abstract

The Wnt/β-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer’s disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3β S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-β oligomers (AβO) in mice. Finally, quercitrin rescues AβO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/β-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.

Therapeutic Potential of Natural Compounds from Herbs and Nutraceuticals in Alleviating Neurological Disorders: Targeting the Wnt Signaling Pathway

“…69 The lack of Wnt/β-catenin pathway signaling can indirectly promote neuroinflammation during aging, thus further promoting the development of AD. 70 Triggering receptors expressed on myeloid cells 2 (TREM2) activate microglia aggregation around plaques, thereby limiting Aβ diffusion and subsequent toxicity. Notably, TREM2 promotes microglia survival by activating the Wnt/β-catenin signaling pathway, indicating that the Wnt pathway is required for proper clearance of Aβ deposits.…”

“…Therefore, their results revealed that quercitrin serves as a Wnt/β-catenin signaling pathway enhancer, which opens up new avenues for the treatment of AD. 70 Icariin II, one of the main active components of Herba Epimedii, has been shown to promote osteogenic differentiation of bone marrow-derived stromal cells. 157 It conveys a protective effect against brain I/R injury and cognitive deficits.…”

“…Neuroinflammation driven by microglia and astrocytes plays an important role in the pathogenesis of AD . The lack of Wnt/β-catenin pathway signaling can indirectly promote neuroinflammation during aging, thus further promoting the development of AD . Triggering receptors expressed on myeloid cells 2 (TREM2) activate microglia aggregation around plaques, thereby limiting Aβ diffusion and subsequent toxicity.…”

“…XAV939 is a downstream inhibitor of GSK3, which can prevent a series of neuroprotective effects mediated by quercitrin. Therefore, their results revealed that quercitrin serves as a Wnt/β-catenin signaling pathway enhancer, which opens up new avenues for the treatment of AD …”

A high-performance liquid chromatography method validation and a Box–Behnken experimental design for the extraction optimization of quercitrin from Nectandra reticulata

“…2 Quercitrin has anti-inflammatory, anti-leishmanial, osteogenic, anti-nociceptive, and neuroprotective properties. 3 Research has shown that quercitrin inhibits GSK3 and enhances the signaling pathway Wnt/catenin. 3 Moreover, quercitrin has antioxidant and free radical scavenger activity, 4 and it inhibits acetylcholinesterase.…”