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Updated: Sep 12, 2026
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
ZDWX-25, a dual DYRK1A/GSK3β inhibitor, attenuates tau hyperphosphorylation and neuroinflammation in acute mouse
Weiyi Wang1, Yu Xing1, Zonghe Xu1
1Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China.
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.