Inhibitors of Class 1 Histone Deacetylases Reverse Contextual Memory Deficits in a Mouse Model of Alzheimer’s Disease.

Bibliographic

Year of Publication: 
2010
Contact PI Name: 
Gavin Rumbaugh
Contact PI Affiliation: 
Department of Neurobiology, Evelyn F McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL, USA
Co-Authors: 
Mark Kilgore, Courtney A Miller, Daniel M Fass, Krista M Hennig, Stephen J Haggarty, J David Sweatt
Primary Reference (PubMED ID): 
Funding Source:
Study Goal and Principal Findings: 

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized clinically by cognitive impairments that progress to dementia and death. The earliest symptoms of AD present as a relatively pure deficit in memory retrieval. Therefore, drug treatments that intervene in the early stages of AD by rescuing memory deficits could be promising therapies to slow, or even reverse progression of the disease. In this study, we tested the potential of systemic histone deacetylase inhibitor (HDACi) treatment to rescue cognitive deficits in a mouse model of AD. APPswe/PS1dE9 mice showed pronounced contextual memory impairments beginning at 6 months of age. Chronic HDACi injections (2–3 weeks) did not alter contextual memory formation in normal mice, but had profound effects in transgenic animals. Injections of sodium valproate, sodium butyrate, or vorinostat (suberoylanilide hydroxamic acid; Zolinzas) completely restored contextual memory in these mutant mice. Further behavioral testing of the HDACi-treated transgenic mice showed that the newly consolidated memories were stably maintained over a 2-week period. Measurement of the HDAC isoform selectivity profile of sodium valproate, sodium butyrate, and vorinostat revealed the common inhibition of class I HDACs (HDAC1, 2, 3, 8) with little effect on the class IIa HDAC family members (HDAC4, 5, 7, 9) and inhibition of HDAC6 only by vorinostat. These preclinical results indicate that targeted inhibition of class I HDAC isoforms is a promising avenue for treating the cognitive deficits associated with early stage AD.

Therapeutic Agent

Therapeutic Information: 
Therapy Type:
Therapy Type:
Therapy Type:

Animal Model

Model Information: 
Species:
Model Type:
Strain/Genetic Background: 
C57BL/6

Experimental Design

Is the following information reported in the study?: 
Power/Sample Size Calculation
Blinded for Treatment
Pharmacokinetic Measures
Toxicology Measures
Biomarkers
Formulation
Duration of Treatment
Age of Animal at the Beginning of Treatment
Sex as a Biological Variable
Number of Premature Deaths
Statistical Plan
Inclusion/Exclusion Criteria Included
Randomized into Groups
Blinded for Outcome Measures
Pharmacodynamic Measures
ADME Measures
Dose
Route of Delivery
Frequency of Administration
Age of Animal at the End of Treatment
Study Balanced for Sex as a Biological Variable
Number of Excluded Animals
Genetic Background
Conflict of Interest

Outcomes

Outcomes: 
Outcome MeasuredOutcome Parameters
Behavioral
  • Contextual Fear Conditioning
  • Exploratory Activity
  • Biochemical
  • Acetyl-Histone H4 (H4ac)
  • Histone H3
  • IC50
  • Pharmacodynamics
  • Target Engagement (inhibition Histone deacetylases)