Tubastatin A/ACY-1215 improves cognition in Alzheimer's disease transgenic mice

J Alzheimers Dis. 2014;41(4):1193-205. doi: 10.3233/JAD-140066.


Histone deacetylase 6 (HDAC6) is currently being discussed as a promising therapeutic target for the treatment of Alzheimer's disease (AD). Mounting evidence indicates that increased HDAC6 expression may contribute to AD-associated neurodegeneration, although beneficial effects have also been identified. In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. Further, the decreased hyperphosphorylated tau and increased tubulin acetylation may account for the improved microtubule stability in AD mice after tubastatin A/ACY-1215 treatment. These preclinical results support the detrimental role of HDAC6 in AD, and offer prospective approaches for using tubastatin A/ACY-1215 as potential therapeutic strategy for AD.

Keywords: Alzheimer's disease; amyloid; autophagy; histone deacetylase (HDAC); tau.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications*
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / drug effects
  • Brain / pathology
  • Brain / ultrastructure
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology*
  • Disease Models, Animal
  • Exploratory Behavior / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / therapeutic use*
  • Indoles / therapeutic use*
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptide Fragments / metabolism
  • Phosphorylation / drug effects
  • Presenilin-1 / genetics
  • Pyrimidines / therapeutic use*
  • Tubulin / genetics
  • Tubulin / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • Pyrimidines
  • Tubulin
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • tubastatin A
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases
  • ricolinostat