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An Epigenetic Blockade of Cognitive Functions in the Neurodegenerating Brain

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 neu... Full description

Journal Title: Gräff Johannes, Damien Rei, Ji-Song Guan, Wen-Yuan Wang, Jinsoo Seo, Krista M. Hennig, Thomas Nieland, et al. 2012. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483(7388): 222-226.
Main Author: Gräff, Johannes
Other Authors: Rei, Damien , Guan, Ji-Song , Wang, Wen-Yuan , Seo, Jinsoo , Fass, Daniel M. , Kao, Patricia F. , Kahn, Martin , Su, Susan C. , Joseph, Nadine , Delalle, Ivana , Tsai, Li-Huei , Hennig, Krista M. , Nieland, Thomas , Samiei, Alireza , Haggarty, Stephen John
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0028-0836 ; DOI: 10.1038/nature10849
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recordid: dash1/10579390
title: An Epigenetic Blockade of Cognitive Functions in the Neurodegenerating Brain
format: Article
creator:
  • Gräff, Johannes
  • Rei, Damien
  • Guan, Ji-Song
  • Wang, Wen-Yuan
  • Seo, Jinsoo
  • Fass, Daniel M.
  • Kao, Patricia F.
  • Kahn, Martin
  • Su, Susan C.
  • Joseph, Nadine
  • Delalle, Ivana
  • Tsai, Li-Huei
  • Hennig, Krista M.
  • Nieland, Thomas
  • Samiei, Alireza
  • Haggarty, Stephen John
subjects:
  • Neuroscience
  • Disease
  • Molecular Biology
  • Animal Behavior
ispartof: Gräff, Johannes, Damien Rei, Ji-Song Guan, Wen-Yuan Wang, Jinsoo Seo, Krista M. Hennig, Thomas Nieland, et al. 2012. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483(7388): 222-226.
description: 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.
language: eng
source:
identifier: ISSN: 0028-0836 ; DOI: 10.1038/nature10849
fulltext: fulltext_linktorsrc
issn:
  • 0028-0836
  • 1476-4687
  • 00280836
  • 14764687
url: Link


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titleAn Epigenetic Blockade of Cognitive Functions in the Neurodegenerating Brain
creatorGräff, Johannes ; Rei, Damien ; Guan, Ji-Song ; Wang, Wen-Yuan ; Seo, Jinsoo ; Fass, Daniel M. ; Kao, Patricia F. ; Kahn, Martin ; Su, Susan C. ; Joseph, Nadine ; Delalle, Ivana ; Tsai, Li-Huei ; Hennig, Krista M. ; Nieland, Thomas ; Samiei, Alireza ; Haggarty, Stephen John
ispartofGräff, Johannes, Damien Rei, Ji-Song Guan, Wen-Yuan Wang, Jinsoo Seo, Krista M. Hennig, Thomas Nieland, et al. 2012. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483(7388): 222-226.
identifierISSN: 0028-0836 ; DOI: 10.1038/nature10849
subjectNeuroscience ; Disease ; Molecular Biology ; Animal Behavior
descriptionCognitive 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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titleAn Epigenetic Blockade of Cognitive Functions in the Neurodegenerating Brain
descriptionCognitive 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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abstractCognitive 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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