An epigenetic blockade of cognitive functions in the neurodegenerating brain.

Nature
Authors
Keywords
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.

Year of Publication
2012
Journal
Nature
Volume
483
Issue
7388
Pages
222-6
Date Published
2012 Feb 29
ISSN
1476-4687
URL
DOI
10.1038/nature10849
PubMed ID
22388814
PubMed Central ID
PMC3498952
Links
Grant list
R01DA028301 / DA / NIDA NIH HHS / United States
R01 NS078839 / NS / NINDS NIH HHS / United States
Howard Hughes Medical Institute / United States
R01NS078839 / NS / NINDS NIH HHS / United States
R01 DA028301 / DA / NIDA NIH HHS / United States
R01 MH095088 / MH / NIMH NIH HHS / United States