ArticleFrontiers in pharmacology2026
ZDWX-25, a dual DYRK1A/GSK3β inhibitor, attenuates tau hyperphosphorylation and neuroinflammation in acute mouse models.
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Objective: This study investigates the mechanisms of ZDWX-25, a novel dual DYRK1A/GSK3β inhibitor, in alleviating tau pathology and explores its potential anti-neuroinflammatory effects. Methods: Acute tauopathy was induced by okadaic acid (OKA) and neuroinflammation by lipopolysaccharide (LPS) in mice. Cognitive function was assessed by Morris water maze and Y-maze (OKA only). Tau phosphorylation (AT8), neuronal integrity (Nissl, PSD95), microglial activation (IBA-1), and inflammatory mediators were measured. The PI3K inhibitor LY294002 was used in HT22 and BV2 cells. Results: In the OKA model, ZDWX-25 improved spatial and working memory, reduced tau hyperphosphorylation, and protected neurons. It activated PI3K/AKT; LY294002 completely blocked the GSK3β inhibitor AR-A014418, whereas both the DYRK1A inhibitor harmine and ZDWX-25 retained significant, albeit reduced, efficacy, revealing direct (PI3K/AKT-independent) GSK3β inhibition plus indirect (DYRK1A→PI3K/AKT) enhancement. ZDWX-25 also promoted microglial tau phagocytosis. In the LPS model, ZDWX-25 suppressed microglial activation and inflammatory mediators (IL-6, TNF-α, iNOS) and ameliorated cognitive deficits. Conclusion: ZDWX-25 attenuates tau pathology via dual direct/indirect mechanisms and enhances microglial clearance; it also shows preliminary anti-neuroinflammatory effects. These findings support ZDWX-25 as a multi-target candidate for Alzheimer's disease.
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