title: Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression.
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.
  
  
  CONCLUSIONS
  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 FDA-approved for other uses.
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Rd,, Jacksonville, Florida 32224, USA. Dickey.chad@mayo.edu
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
authors.forename: Peter
authors.initials: P
authors.lastname: Ash
authors.forename: Natalia
authors.initials: N
authors.lastname: Klosak
authors.forename: Wing C
authors.initials: WC
authors.lastname: Lee
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Eckman