Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease1. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge2. 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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We thank A. Mungenast, S. Jemielity, R. Madabushi, F. Calderon de Anda and M. Horn for reading the manuscript, A.M. for manuscript editing, M. Eichler for mouse colony maintenance, K. Fitch for sectioning the human brain samples and M.H. for quantification of Fig. 2a. This work was partly supported by the Stanley Medical Research Institution (to S.J.H. and L.-H.T.), National Institutes of Health/National Institute on Drug Abuse (RO1DA028301, to S.J.H.) and National Institutes of Health/National Institute of Neurological Disorders and Stroke (RO1NS078839, to L.-H.T.). J.G. was supported by a Bard Richmond fellowship and by the Swiss National Science Foundation, W.Y.W. by the Simons Foundation and M.K. by the Theodor und Ida Herzog-Egli foundation. L.-H.T. is an investigator of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
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Gräff, J., Rei, D., Guan, JS. et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483, 222–226 (2012). https://doi.org/10.1038/nature10849
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