title: Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition.
abstract: BACKGROUND
  Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy.
  
  
  METHODS
  We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume).
  
  
  RESULTS
  We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically.
  
  
  CONCLUSIONS
  Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology.
authors.affiliation: Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA ; College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Maj-Linda
authors.initials: ML
authors.lastname: Selenica
authors.affiliation: Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Leif
authors.initials: L
authors.lastname: Benner
authors.affiliation: Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Housley
authors.affiliation: Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Manchec
authors.affiliation: Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA ; College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Lee
authors.affiliation: Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA ; College of Medicine, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Nash
authors.affiliation: Department of Pharmacology and Molecular Science, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Kalin
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Bergman
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Kozikowski
authors.affiliation: Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA ; College of Medicine, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Marcia N
authors.initials: MN
authors.lastname: Gordon
authors.affiliation: Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA ; College of Medicine, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Morgan