Article

An epigenetic blockade of cognitive functions in the neurodegenerating brain

Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nature (Impact Factor: 42.35). 03/2012; 483(7388):222-6. DOI: 10.1038/nature10849
Source: PubMed

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.

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    • "Marcelo Wood and colleagues have found Brg1-associated factor chromatin remodeling complexes to be necessary for memory and synaptic plasticity (Vogel-Ciernia et al., 2013). Li-Huei Tsai and colleagues have found that histone deacetylase (HDAC) inhibitors can effectively reestablish access to memories after neurodegeneration (Graff et al., 2012, 2014; Rudenko and Tsai, 2014). There is even evidence that certain exposures can lead to intergenerational inheritance of behavioral phenotypes (Byrnes et al., 2011; Dias and Ressler, 2014; Gapp et al., 2014; Szutorisz et al., 2014; Vassoler et al., 2013). "
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    • "The cause of AD is still not well understood and there is no disease-modifying treatment to delay onset or slow progression [2] [3]. Epigenetics of AD is a growing field that has gained interest due to the repression of gene transcription, an epigenetic blockade, that is consistently observed in AD [4] [5]. Among these changes associated with gene repression are post-translational modifications (PTMs) of histones, which can alter histone–DNA and inter-nucleosome interaction and, in turn, chromatin structure [6]. "
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    • "Bakulski et al. [171] sheds light on the molecular mechanism involved in late-onset Alzheimer's disease (LOAD) using genome-wide DNA methylation array in which discordant DNA methylation were observed in LOAD cases. Besides DNA methylation, the patterns of histone modification including low level of H3 acetylation [172] and increased level of HDAC6 and HDAC2 were seen in post-mortem AD brain [173] [174]. DNA methylation signatures were observed in a number of studies in Parkinson disease (PD) genes in post-mortem brain and peripheral blood cells [175]. "
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