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Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease

Academic Article
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Overview

authors

  • Kilgore, M.
  • Miller, Courtney
  • Fass, D. M.
  • Hennig, K. M.
  • Haggarty, S. J.
  • Sweatt, J. D.
  • Rumbaugh, Gavin

publication date

  • March 2010

journal

  • Neuropsychopharmacology  Journal

abstract

  • 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; Zolinza) 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.

subject areas

  • Alzheimer Disease
  • Amyloid beta-Protein Precursor
  • Analysis of Variance
  • Animals
  • Conditioning, Classical
  • Disease Models, Animal
  • Enzyme Inhibitors
  • Fear
  • Female
  • Hippocampus
  • Histone Deacetylase 1
  • Humans
  • In Vitro Techniques
  • Male
  • Memory Disorders
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Presenilin-1
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Research

keywords

  • Alzheimer's disease
  • cognition
  • drug discovery
  • epigenetics
  • fear memory
  • histone deacetylase inhibitor
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Identity

PubMed Central ID

  • PMC3055373

International Standard Serial Number (ISSN)

  • 0893-133X

Digital Object Identifier (DOI)

  • 10.1038/npp.2009.197

PubMed ID

  • 20010553
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Additional Document Info

start page

  • 870

end page

  • 880

volume

  • 35

issue

  • 4

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