Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression

35Citations
Citations of this article
34Readers
Mendeley users who have this article in their library.

Abstract

The microtubule-associated protein tau (MAPT) is a pathological component of several neurodegenerative diseases and clinical dementias. Here, we have investigated the effects of a series of commercially available FDA-approved compounds and natural products on total tau protein levels using a cell-based approach that allows for the rapid and efficient measurement of changes in protein expression. Results: The compounds that reduced tau largely fell within 3 functional categories with the largest percentage being microtubule regulators. Several of these candidates were validated in both a human neuroglioma and a human neuroblastoma cell line. While these drugs lead to a rapid reduction in tau protein levels, a selective decrease in MAPT mRNA expression was also observed. Conclusion: These findings suggest that the identified compounds that reduce tau levels may act either through direct effects on the MAPT promoter itself or by altering a feedback transcriptional mechanism regulating MAPT transcription. This is particularly interesting in light of recent evidence suggesting that MAPT 5' UTR mutations in late-onset PD and PSP cases alter the expression of tau mRNA. In fact, one of the compounds we identified, rotenone, has been used extensively to model PD in rodents. These observations may provide key insights into the mechanism of tau turnover within the neuron while also providing the first evidence that selectively reducing tau protein levels may be possible using compounds that are PDA-approved for other uses.

Cite

CITATION STYLE

APA

Dickey, C. A., Ash, P., Klosak, N., Lee, W. C., Petrucelli, L., Hutton, M., & Eckman, C. B. (2006). Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Molecular Neurodegeneration, 1(1). https://doi.org/10.1186/1750-1326-1-6

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free