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Wnt Signaling Rescues Amyloid Beta-Induced Gut Stem Cell Loss.

ABSTRACT: Patients with Alzheimer's disease suffer from a decrease in brain mass and a prevalence of amyloid-β plaques. These plaques are thought to play a role in disease progression, but their exact role is not entirely established. We developed an optogenetic model to induce amyloid-β intracellular oligomerization to model distinct disease etiologies. Here, we examine the effect of Wnt signaling on amyloid in an optogenetic, Drosophila gut stem cell model. We observe that Wnt activation rescues the detrimental effects of amyloid expression and oligomerization. We analyze the gene expression changes downstream of Wnt that contribute to this rescue and find changes in aging related genes, protein misfolding, metabolism, and inflammation. We propose that Wnt expression reduces inflammation through repression of Toll activating factors. We confirm that chronic Toll activation reduces lifespan, but a decrease in the upstream activator Persephone extends it. We propose that the protective effect observed for lithium treatment functions, at least in part, through Wnt activation and the inhibition of inflammation.

SUBMITTER: Kaur P

PROVIDER: S-EPMC8774390 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Wnt Signaling Rescues Amyloid Beta-Induced Gut Stem Cell Loss

Project description:Wnt signaling has well established roles in development and cancer progression. Its roles during normal adult homeostasis are less well studied, but Wnt is a major stem cell regulating factor in adult tissues. Here we use an optogenetic model of amyloid beta aggregation to examine the effect of Wnt signaling on protein aggregation. We observe that Wnt activation rescues the detrimental effects of Amyloid. We analyze the gene expression changes downstream of Wnt that contribute to this rescue and find a protein misfolding response and a metabolic response, but the major factor we focus on is inflammation. Wnt expression reduces inflammation through repression of Toll activating factors, and chronic Toll activation reduces lifespan. We propose that the protective effect observed for lithium treatment functions at least in part through Wnt activation and inhibition of inflammation.

2021-12-31 | GSE181844 | GEO

Wnt Signaling Rescues Amyloid Beta-Induced Gut Stem Cell Loss

Project description:Wnt Signaling Rescues Amyloid Beta-Induced Gut Stem Cell Loss

| PRJNA753593 | ENA

SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology.

Project description:Amyloid-β oligomers (AβOs), toxic peptide aggregates found in Alzheimer's disease, cause synapse pathology. AβOs interact with neurexins (NRXs), key synaptic organizers, and this interaction dampens normal trafficking and function of NRXs. Axonal trafficking of NRX is in part regulated by its interaction with SorCS1, a protein sorting receptor, but the impact of SorCS1 regulation of NRXs in Aβ pathology was previously unstudied. Here, we show competition between the SorCS1 ectodomain and AβOs for β-NRX binding and rescue effects of the SorCS1b isoform on AβO-induced synaptic pathology. Like AβOs, the SorCS1 ectodomain binds to NRX1β through the histidine-rich domain of NRX1β, and the SorCS1 ectodomain and AβOs compete for NRX1β binding. In cultured hippocampal neurons, SorCS1b colocalizes with NRX1β on the axon surface, and axonal expression of SorCS1b rescues AβO-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling and AβO-induced structural defects in excitatory synapses. Thus, our data suggest a role for SorCS1 in the rescue of AβO-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for Alzheimer's disease.

| S-EPMC9880023 | biostudies-literature

Wnt/beta-catenin signaling in embryonic stem cell converted tumor cells.

Project description:BackgroundEmbryonic stem cells (ESCs) are pluripotent stem cells and can form tumors containing cells from all three germ layers. Similarities between pluripotent stem cells and malignant tumor cells have been identified. The purpose of this study was to obtain ESCs-converted tumor cell lines and to investigate the mechanism of malignancy in pluripotent stem cells.MethodsMouse ESCs were subcutaneously injected into nude mice to obtain tumors from which a tumor-like cell line (ECCs1) was established by culturing the cells in chemical-defined N2B27 medium supplied with two small molecular inhibitors CHIR99021 and PD0325901 (2i). The ECCs1 were then subcutaneously injected into nude mice again to obtain tumors from which another tumor-like cells line (ECCs2) was established in the same 2i medium. The malignant degree of ESCs, ECCs1 and ECCs2 was compared and the underlying mechanism involved in the malignancy development of ESCs was examined.ResultsThe three ESCs, ECCs1 and ECCs2 cell lines were cultured in the same 2i condition and showed some likeness such as Oct4-expression and long-term expansion ability. However, the morphology and the tumor-formation ability of the cell lines were different. We identified that ECCs1 and ECCs2 gradually acquired malignancy. Moreover, Wnt signaling-related genes such as CD133 and ?-catenin expression were up-regulated and Frizzled related protein (FRP) was down-regulated during the tumor development of ESCs.ConclusionsThe two tumor-like cell lines ECCs1 and ECCs2 stand for early malignant development stage of ESCs and the ECCs2 was more malignant than the ECCs1. Moreover, we identified that Wnt/?-catenin signaling played an important role in the malignancy process of ESCs.

| S-EPMC3515512 | biostudies-literature

Chronic-Antibiotics Induced Gut Microbiota Dysbiosis Rescues Memory Impairment and Reduces β-Amyloid Aggregation in a Preclinical Alzheimer's Disease Model.

Project description:Alzheimer's disease (AD) is a multifactorial pathology characterized by β-amyloid (Aβ) deposits, Tau hyperphosphorylation, neuroinflammatory response, and cognitive deficit. Changes in the bacterial gut microbiota (BGM) have been reported as a possible etiological factor of AD. We assessed in offspring (F1) 3xTg, the effect of BGM dysbiosisdysbiosis in mothers (F0) at gestation and F1 from lactation up to the age of 5 months on Aβ and Tau levels in the hippocampus, as well as on spatial memory at the early symptomatic stage of AD. We found that BGM dysbiosisdysbiosis with antibiotics (Abx) treatment in F0 was vertically transferred to their F1 3xTg mice, as observed on postnatal day (PD) 30 and 150. On PD150, we observed a delay in spatial memory impairment and Aβ deposits, but not in Tau and pTau protein in the hippocampus at the early symptomatic stage of AD. These effects are correlated with relative abundance of bacteria and alpha diversity, and are specific to bacterial consortia. Our results suggest that this specific BGM could reduce neuroinflammatory responses related to cerebral amyloidosis and cognitive deficit and activate metabolic pathways associated with the biosynthesis of triggering or protective molecules for AD.

| S-EPMC9331718 | biostudies-literature

HIF-1α Affects the Neural Stem Cell Differentiation of Human Induced Pluripotent Stem Cells via MFN2-Mediated Wnt/β-Catenin Signaling.

Project description:Hypoxia-inducible factor 1α (HIF-1α) plays pivotal roles in maintaining pluripotency, and the developmental potential of pluripotent stem cells (PSCs). However, the mechanisms underlying HIF-1α regulation of neural stem cell (NSC) differentiation of human induced pluripotent stem cells (hiPSCs) remains unclear. In this study, we demonstrated that HIF-1α knockdown significantly inhibits the pluripotency and self-renewal potential of hiPSCs. We further uncovered that the disruption of HIF-1α promotes the NSC differentiation and development potential in vitro and in vivo. Mechanistically, HIF-1α knockdown significantly enhances mitofusin2 (MFN2)-mediated Wnt/β-catenin signaling, and excessive mitochondrial fusion could also promote the NSC differentiation potential of hiPSCs via activating the β-catenin signaling. Additionally, MFN2 significantly reverses the effects of HIF-1α overexpression on the NSC differentiation potential and β-catenin activity of hiPSCs. Furthermore, Wnt/β-catenin signaling inhibition could also reverse the effects of HIF-1α knockdown on the NSC differentiation potential of hiPSCs. This study provided a novel strategy for improving the directed differentiation efficiency of functional NSCs. These findings are important for the development of potential clinical interventions for neurological diseases caused by metabolic disorders.

| S-EPMC8256873 | biostudies-literature

Primary cilia regulate gastric cancer-induced bone loss via cilia/Wnt/β-catenin signaling pathway.

Project description:Cancer-associated bone disease is a frequent occurrence in cancer patients and is associated with pain, bone fragility, loss, and fractures. However, whether primary or non-bone metastatic gastric cancer induces bone loss remains unclear. Here, we collected clinical evidence of bone loss by analyzing serum and X-rays of 25 non-bone metastatic gastric cancer patients. In addition, C57BL mice were injected with the human gastric cancer cell line HGC27 and its effect on bone mass was analyzed by Micro-CT, immunoblotting, and immunohistochemistry. Furthermore, the degree of the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) co-cultured with HGC-27 or SGC-7901 cells was analyzed by colony-formation assay, alizarin red staining, immunofluorescence, qPCR, immunoblotting, and alkaline phosphatase activity assay. These indicated that gastric cancer could damage bone tissue before the occurrence of bone metastases. We also found that cilia formation of MSCs was increased in the presence of HGC27 cells, which was associated with abnormal activation of the Wnt/β-catenin pathway. Expression of DKK1 inhibited the Wnt/β-catenin signaling pathway and partially rescued osteogenic differentiation of MSCs. In summary, our results suggest that gastric cancer cells might cause bone damage prior to the occurrence of bone metastasis via cilia-dependent activation of the Wnt/β-catenin signaling pathway.

| S-EPMC8034975 | biostudies-literature

Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency.

Project description:Embryonic stem cells (ESCs) represent an important research tool and a potential resource for regenerative medicine. Generally, ESCs are cocultured with a supportive feeder cell layer of murine embryonic fibroblasts, which maintain the ESCs' capacity for self-renewal and block spontaneous differentiation. These cumbersome conditions, as well as the risk of xenobiotic contamination of human ESCs grown on murine embryonic fibroblasts, make it a priority to develop chemically defined methods that can be safely used for the expansion of ESCs. Using a high-throughput, cell-based assay, we identified the small molecule IQ-1 that allows for the Wnt/beta-catenin-driven long-term expansion of mouse ESCs and prevents spontaneous differentiation. We demonstrate that IQ-1, by targeting the PR72/130 subunit of the serine/threonine phosphatase PP2A, prevents beta-catenin from switching coactivator usage from CBP to p300. The increase in beta-catenin/CBP-mediated transcription at the expense of beta-catenin/p300-mediated transcription is critical for the maintenance of murine stem cell pluripotency.

| S-EPMC1838514 | biostudies-literature

Wnt signaling regulates pancreatic beta cell proliferation.

Project description:There is widespread interest in defining factors and mechanisms that stimulate proliferation of pancreatic islet cells. Wnt signaling is an important regulator of organ growth and cell fates, and genes encoding Wnt-signaling factors are expressed in the pancreas. However, it is unclear whether Wnt signaling regulates pancreatic islet proliferation and differentiation. Here we provide evidence that Wnt signaling stimulates islet beta cell proliferation. The addition of purified Wnt3a protein to cultured beta cells or islets promoted expression of Pitx2, a direct target of Wnt signaling, and Cyclin D2, an essential regulator of beta cell cycle progression, and led to increased beta cell proliferation in vitro. Conditional pancreatic beta cell expression of activated beta-catenin, a crucial Wnt signal transduction protein, produced similar phenotypes in vivo, leading to beta cell expansion, increased insulin production and serum levels, and enhanced glucose handling. Conditional beta cell expression of Axin, a potent negative regulator of Wnt signaling, led to reduced Pitx2 and Cyclin D2 expression by beta cells, resulting in reduced neonatal beta cell expansion and mass and impaired glucose tolerance. Thus, Wnt signaling is both necessary and sufficient for islet beta cell proliferation, and our study provides previously unrecognized evidence of a mechanism governing endocrine pancreas growth and function.

| S-EPMC1847455 | biostudies-literature

A role for APP in Wnt signalling links synapse loss with β-amyloid production.

Project description:In Alzheimer's disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by β-amyloid (Aβ) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-β-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aβ-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability. Furthermore, activation of non-canonical Wnt signalling enhances Aβ production, while activation of canonical signalling suppresses Aβ production. Together, these findings identify a pathogenic-positive feedback loop in which Aβ induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further Aβ production. The Swedish familial AD variant of APP (APPSwe) more readily co-activates non-canonical, at the expense of canonical Wnt activity, indicating that its pathogenicity likely involves direct effects on synapses, in addition to increased Aβ production. Finally, we report that pharmacological inhibition of the Aβ-Dkk1-Aβ positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce Aβ load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between Aβ accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.

| S-EPMC6145937 | biostudies-literature

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