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Updated: Dec 18, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Tolfenamic acid inhibits GSK-3β and PP2A mediated tau hyperphosphorylation in Alzheimer's disease models
Huiming Zhang1, Xiaojuan Wang1, Pu Xu1
1Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China.
Abstract:
Tolfenamic acid, a nonsteroidal anti-inflammatory drug, alleviated learning and memory deficits and decreased the expression of specificity protein 1 (SP1)-mediated cyclin-dependent kinase-5 (CDK5), a major protein kinase that regulates hyperphosphorylated tau, in Alzheimer's disease (AD) transgenic mice. However, whether tolfenamic acid can regulate the major tau protein kinase, glycogen synthase kinase-3β (GSK-3β), or tau protein phosphatase, protein phosphatase 2A (PP2A), further inhibiting hyperphosphorylation of tau, remains unknown. To this end, tolfenamic acid was administered i.p. in a GSK-3β overactivation postnatal rat model and orally in mice after intracerebroventricular (ICV) injection of okadaic acid (OA) to develop a PP2A inhibition model. We used four behavioural experiments to evaluate memory function in ICV-OA mice. In this study, tolfenamic acid attenuated memory dysfunction. Tolfenamic acid decreased the expression of hyperphosphorylated tau in the brain by inhibiting GSK-3β activity, decreasing phosphorylated PP2A (Tyr307), and enhancing PP2A activity. Tolfenamic acid also increased wortmannin (WT) and GF-109203X (GFX) induced phosphorylation of GSK-3β (Ser9) and prevented OA-induced downregulation of PP2A activity in PC12 cells. Altogether, these results show that tolfenamic acid not only decreased SP1/CDK5-mediated tau phosphorylation, but also inhibited GSK-3β and PP2A-mediated tau hyperphosphorylation in AD models.
Insights
Tolfenamic acid, an anti-inflammatory drug, improved memory in Alzheimer's disease models by reducing tau protein phosphorylation. It targets key enzymes like GSK-3β and PP2A, offering a potential therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by hyperphosphorylated tau protein.
- Specificity protein 1 (SP1)-mediated cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK-3β) are implicated in tau hyperphosphorylation.
- Protein phosphatase 2A (PP2A) plays a crucial role in dephosphorylating tau.
Purpose of the Study:
- To investigate the effects of tolfenamic acid on GSK-3β and PP2A in Alzheimer's disease models.
- To determine if tolfenamic acid can inhibit tau hyperphosphorylation by modulating GSK-3β and PP2A activity.
Main Methods:
- Tolfenamic acid was administered to postnatal rats with overactivated GSK-3β and to mice with okadaic acid (OA)-induced PP2A inhibition.
- Behavioral experiments assessed memory function in ICV-OA mice.
- Western blotting and enzyme activity assays were used to analyze protein expression and activity in brain tissue and PC12 cells.
Main Results:
- Tolfenamic acid attenuated memory dysfunction in ICV-OA mice.
- It decreased hyperphosphorylated tau by inhibiting GSK-3β activity and decreasing phosphorylated PP2A (Tyr307).
- Tolfenamic acid enhanced PP2A activity and prevented OA-induced PP2A downregulation in PC12 cells.
Conclusions:
- Tolfenamic acid reduces tau hyperphosphorylation through multiple pathways, including inhibiting GSK-3β and modulating PP2A activity.
- Beyond SP1/CDK5, tolfenamic acid targets GSK-3β and PP2A to combat tau hyperphosphorylation in AD models.
- These findings suggest tolfenamic acid as a potential therapeutic agent for Alzheimer's disease.
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