Tolfenamic acid inhibits GSK-3β and PP2A mediated tau hyperphosphorylation in Alzheimer’s disease models

The journal of physiological sciences

article

Huiming Zhang¹  Xiaojuan Wang¹  Pu Xu¹  Xuefei Ji¹  Tianyan Chi¹  Peng Liu¹  Libo Zou¹ 

[1] Department of Pharmacology, Shenyang Pharmaceutical University

关键词: Alzheimer’s disease;    Glycogen synthase kinase-3β;    Protein phosphatase 2A;    Tau hyperphosphorylation;    Tolfenamic acid;   

DOI  :  10.1186/s12576-020-00757-y

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown