ZDWX-25, a dual DYRK1A/GSK3β inhibitor, attenuates tau hyperphosphorylation and neuroinflammation in acute mouse models.

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.