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Nature DOI:10.1038/nature10849

An epigenetic blockade of cognitive functions in the neurodegenerating brain.

Publication TypeJournal Article
Year of Publication2012
AuthorsGräff, J, Rei, D, Guan, J-S, Wang, W-Y, Seo, J, Hennig, KM, Nieland, TJF, Fass, DM, Kao, PF, Kahn, M, Su, SC, Samiei, A, Joseph, N, Haggarty, SJ, Delalle, I, Tsai, L-H
Date Published2012 Feb 29
KeywordsAcetylation, 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, Receptors, Glucocorticoid, RNA Polymerase II

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.


Alternate JournalNature
PubMed ID22388814
PubMed Central IDPMC3498952
Grant ListR01DA028301 / 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