Efficacy Measures of Tolfenamic Acid in a Tau Knock Out Model: Relevance to Alzheimer's Disease

Allison Leso, University of Rhode Island

Abstract

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), amyloid-beta (Aβ) plaques and tau tangles. Multiple neurodegenerative diseases, termed tauopathies, such as Pick’s disease, and progressive supranuclear palsy (PSP), are also linked to mutations in tau. While AD does include a second hallmark in the form of Aβ plaques, to date all therapeutics aimed at this hallmark have failed. However, the nonsteroidal anti-inflammatory drug (NSAID) tolfenamic acid (TA) has been shown to reduce the levels of multiple neurodegenerative endpoints, and improve cognitive function, in various murine models. Of the murine models tested with TA, all contained some form of the tau gene and the amyloid precursor protein (APP) gene, the precursor of Aβ. The experimental model utilized in this paper, unlike others, tested whether the same positive effects of TA can take place after removal of endogenous murine tau. The impacts of TA, both molecular and behavioral, were no longer significant in the absence of tau. Mice treated with TA, and lacking the tau gene performed no better than their counterparts that were untreated. Additionally, mice treated with TA exhibited no change in levels of neurodegenerative endpoints over those mice that were untreated. Only those mice that were treated with TA while concurrently possessing the tau gene exhibited improved cognitive function and lower pathological burden. This project better identifies links between tau and known neurodegenerative endpoints, and proposes that tau is essential for the action of TA.^

Subject Area

Neurosciences|Pharmaceutical sciences

Recommended Citation

Allison Leso, "Efficacy Measures of Tolfenamic Acid in a Tau Knock Out Model: Relevance to Alzheimer's Disease" (2018). Dissertations and Master's Theses (Campus Access). Paper AAI10748686.
http://digitalcommons.uri.edu/dissertations/AAI10748686

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