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An epigenetic blockade of cognitive functions in the neurodegenerating brain.

Abstract

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.

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  • Authors

    Gräff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH

    Institution

    Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

    Source

    Nature 483:7388 2012 Mar 8 pg 222-6

    MeSH

    Acetylation
    Alzheimer Disease
    Amyloid beta-Peptides
    Animals
    Brain
    Disease Models, Animal
    Epigenesis, Genetic
    Gene Expression Regulation
    Gene Knockdown Techniques
    Hippocampus
    Histone Deacetylase 2
    Histones
    Humans
    Hydrogen Peroxide
    Memory Disorders
    Mice
    Neurodegenerative Diseases
    Neuronal Plasticity
    Peptide Fragments
    Phosphorylation
    Promoter Regions, Genetic
    RNA Polymerase II
    Receptors, Glucocorticoid

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22388814