Related Experiment Video
Updated: Jun 7, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
WNT signaling in activated microglia is proinflammatory
Carina Halleskog1, Jan Mulder, Jenny Dahlström
1Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Abstract:
Microglia activation is central to the neuroinflammation associated with neurological and neurodegenerative diseases, particularly because activated microglia are often a source of proinflammatory cytokines. Despite decade-long research, the molecular cascade of proinflammatory transformation of microglia in vivo remains largely elusive. Here, we report increased β-catenin expression, a central intracellular component of WNT signaling, in microglia undergoing a proinflammatory morphogenic transformation under pathogenic conditions associated with neuroinflammation such as Alzheimer's disease. We substantiate disease-associated β-catenin signaling in microglia in vivo by showing age-dependent β-catenin accumulation in mice with Alzheimer's-like pathology (APdE9). In cultured mouse microglia expressing the WNT receptors Frizzled FZD(4,5,7,8) and LDL receptor-related protein 5/6 (LRP5/6), we find that WNT-3A can stabilize β-catenin. WNT-3A dose dependently induces LRP6 phosphorylation with downstream activation of disheveled, β-catenin stabilization, and nuclear import. Gene-expression profiling reveals that WNT-3A stimulation specifically increases the expression of proinflammatory immune response genes in microglia and exacerbates the release of de novo IL-6, IL-12, and tumor necrosis factor α. In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of β-catenin-signaling networks in this cell type.
Insights
WNT signaling, specifically β-catenin, drives proinflammatory changes in microglia, a key process in neuroinflammation and diseases like Alzheimer's. This pathway offers a potential therapeutic target for neurological disorders.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia activation drives neuroinflammation in neurological diseases.
- The molecular mechanisms of microglial proinflammatory transformation are not fully understood.
- Beta-catenin, a WNT signaling component, is implicated in various cellular processes.
Purpose of the Study:
- To investigate the role of beta-catenin and WNT signaling in microglial activation and proinflammatory transformation.
- To elucidate the molecular cascade of WNT signaling in microglia under neuroinflammatory conditions.
- To explore the therapeutic potential of targeting WNT/beta-catenin in neurodegenerative diseases.
Main Methods:
- Studied beta-catenin expression in microglia from Alzheimer's disease models (APdE9 mice).
- Utilized cultured mouse microglia to examine WNT-3A effects on WNT receptor signaling (FZD, LRP5/6).
- Performed gene-expression profiling to assess WNT-3A-induced changes in immune response genes.
Main Results:
- Increased beta-catenin expression observed in microglia from Alzheimer's-like pathology models.
- WNT-3A stimulation stabilized beta-catenin in microglia via LRP6 phosphorylation and downstream signaling.
- WNT-3A upregulated proinflammatory genes (IL-6, IL-12, TNF-α) and exacerbated their release.
Conclusions:
- WNT signaling, mediated by beta-catenin, promotes a proinflammatory phenotype in microglia.
- This pathway is active in disease conditions like Alzheimer's disease.
- Targeting WNT/beta-catenin signaling in microglia may offer a novel therapeutic strategy for neuroinflammation.
Related Concept Videos
02:54Canonical Wnt Signaling Pathway
02:54Canonical Wnt Signaling Pathway
01:38Inflammation
01:41Non-Canonical Wnt Signaling Pathways
01:41Non-Canonical Wnt Signaling Pathways
01:12Chronic Inflammation: Introduction