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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 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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Figure 1: Elevated HDAC2 levels epigenetically block the expression of neuroplasticity genes during neurodegeneration.
Figure 2: Reducing HDAC2 levels alleviates memory deficits.
Figure 3: Neurotoxic insults increase HDAC2 through stress elements in its promoter.
Figure 4: HDAC2 expression is increased in patients with Alzheimer’s disease.

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Acknowledgements

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.

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This study was designed by J.G. and L.-H.T., and directed and coordinated by L.-H.T. J.G. planned and performed the in vitro, CK-p25 and Cdk5cKO mouse and human in vivo biochemical characterization, and all behavioural experiments. D.R. planned and contributed to the in vitro and CK-p25 in vivo experiments, generated the GR526 and the shRNA constructs, and contributed to the stereotaxic injections. J.S.G. initiated and contributed to the CK-p25 biochemical characterization, and performed the 5XFAD and HDAC2−/− experiments. W.Y.W. generated the luciferase constructs. J.S. performed the electrophysiological experiments. K.M.H., T.J.F.N., D.F. and S.J.H. characterized the shRNA constructs. M.K. contributed to the quantitative RT–PCR experiments and performed the quantification of the human data. S.C.S. performed the site-directed mutagenesis. A.S. contributed to the immunohistochemistry and the quantitative reverse transcription/quantitative PCR experiments. N.J. contributed to the behavioural and quantitative reverse transcription/quantitative PCR experiments. P.F.K. and I.D. provided the human samples and contributed to the optimization of their staining. The manuscript was written by J.G. and L.-H.T. and commented on by all authors.

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Correspondence to Li-Huei Tsai.

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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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