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.
Highlights
The World Alzheimer Report in 2018 showed that the number of people with dementia worldwide is currently 50 million, but will reach 152 million in 2050 [1]
Tolfenamic acid attenuated tau hyperphosphorylation in postnatal rats As reported by Selenica et al, Takahashi et al, Leroy and Brion, p-tau and p-glycogen synthase kinase-3β (GSK-3β) levels were increased in the developing rat brain and peaked at postnatal day 12 (P12) [20,21,22]
P12 rats were used for studies of the efficacy of GSK3β inhibition [20]
Summary
The World Alzheimer Report in 2018 showed that the number of people with dementia worldwide is currently 50 million, but will reach 152 million in 2050 [1]. Alzheimer’s disease (AD) is a global threat to human health [2,3,4]. The clinical hallmarks of AD are cognitive and psychiatric dysfunction. The major neuropathological hallmarks of AD are senile plaque deposition, neurofibrillary tangle formation, and neuronal cell loss [2]. The tau protein, a microtubule-associated protein that stabilizes the Specificity protein 1 (Sp1) is a transcription factor, and its target genes include amyloid precursor protein (APP), beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), and CDK5, all of which play vital roles in AD. The regulation of SP1 has an important role in AD therapeutic strategies
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