Loss in efficacy measures of tolfenamic acid in a tau knock-out model: Relevance to Alzheimer’s disease

摘要

In the healthy human brain, the protein tau serves the essential function of stabilizing microtubules. However, in a diseased state, tau becomes destabilized and aggregates into a pathogenic form that ultimately creates one of the two major hallmarks of Alzheimer’s disease (AD), tau tangles. Multiple neurodegenerative diseases, termed tauopathies, such as Pick’s disease, and progressive supranuclear palsy, are also linked to mutations in tau. While AD does include a second hallmark in the form of amyloid beta (Aβ) plaques, to date all therapeutics aimed at these hallmark features have failed. The nonsteroidal anti-inflammatory drug tolfenamic acid (TA) has been shown to reduce the levels of multiple neurodegenerative endpoints viz amyloid precursor protein (APP), Aβ, tau, phosphorylated tau (p-tau) and improve cognitive function, in various murine models, via a new mechanism that targets specificity protein 1 (SP1). Sp1 is a zinc-finger transcription factor essential for the regulation of tau and CDK5 genes (among others). The impact of TA on these neurodegenerative endpoints occurred in animal models and systems in which both the tau and the APP genes were present. The experimental model utilized in this paper tested whether the same beneficial outcomes of TA can take place after the removal of endogenous murine tau. We found that the impact of TA, both molecular and behavioral, was no longer significant in the absence of the tau gene. This ability of TA occurred independently of its action on anti-inflammatory targets. Therefore, these findings suggest the essentiality of tau for the novel mechanism of action of TA.