ABSTRACT
The Wnt/ß-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 GSK3ß 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-ß oligomers (AßO) in mice. Finally, quercitrin rescues AßO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/ß-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.
Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Mice , Animals , Wnt Signaling Pathway , Amyloid beta-Peptides/pharmacology , beta Catenin/metabolism , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Alzheimer Disease/pathology , Quercetin/pharmacology , Quercetin/therapeutic useABSTRACT
Recent studies showed a high diversity of the class Homoscleromorpha (Porifera) in the North Aegean Sea. In the South Aegean Sea, however, only one species of the homoscleromorph genus Plakina, P. weinbergi, was reported so far. Here we describe a new species of Plakina from a marine cave in the South Aegean Sea (Crete Island, Greece), viz., Plakina strongylata sp. nov. The new species is white, fragile, with a highly folded surface, and its spicules are diods, triods and calthrops with rounded extremities plus mono- and dilophose diods, mono-, di- and trilophose triods, and mono-, di, tri- and tetralophose calthrops. The number of Plakina species worldwide is raised to 35, of which nine occur in the Aegean Sea.
