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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway
Author
Predes, Danilo 1   VIAFID ORCID Logo  ; Maia, Lorena A 1 ; Matias, Isadora 1 ; Mota Araujo, Hannah Paola 2 ; Soares, Carolina 2   VIAFID ORCID Logo  ; Fernanda G Q Barros-Aragão 2   VIAFID ORCID Logo  ; Oliveira, Luiz F S 1   VIAFID ORCID Logo  ; Reis, Renata R 1   VIAFID ORCID Logo  ; Amado, Nathalia G 1 ; Simas, Alessandro B C 3 ; Mendes, Fabio A 1   VIAFID ORCID Logo  ; Gomes, Flávia C A 1 ; Figueiredo, Claudia P 2 ; Abreu, Jose G 1   VIAFID ORCID Logo 

 Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil 
 Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil 
 Instituto de Pesquisas de Produtos Naturais Walter Mors, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil 
First page
12078
Publication year
2022
Publication date
2022
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2728490007
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.