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: 41.46). 03/2012; 483(7388):222-6. DOI: 10.1038/nature10849
Source: PubMed


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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Available from: Stephen J Haggarty, Oct 05, 2015
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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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    ABSTRACT: Alzheimer's disease has been shown to have a global reduction in gene expression, called an epigenetic blockade, which may be regulated by histone post-translational modifications. Histone H3 has been shown to be highly regulated by phosphorylation. We, therefore, chose H3 for investigation of phosphorylation of the core sites serine-57 (S57) and threonine-58 (T58). Hemispheres of brains from a mouse model of rapid amyloid deposition (5XFAD) were used for measurement of S57 and T58 phosphorylation. Multiple reaction monitoring (MRM) was used to measure the level of phosphorylation, which was normalized to a non-modified "housekeeping" peptide of H3. S57 phosphorylation was decreased by 40%, T58 phosphorylation was decreased by 45%, and doubly phosphorylated S57pT58p was decreased by 30% in 5XFAD brain in comparison to C57BL/6J age- and sex-matched wild type controls. Amyloid-β (Aβ) and amyloid precursor protein were also measured to confirm that 5XFAD mice produced high levels of Aβ. Decreased phosphorylation of these sites in close proximity to DNA may lead to stabilization of DNA-histone interactions and a condensed chromatin state, consistent with the epigenetic blockade associated with AD. Our findings of H3 sites S57 and T58 exhibiting lower levels of phosphorylation in 5XFAD model compared to wild type control implicate these sites in the epigenetic blockade in neurodegeneration pathology.
    FEBS Open Bio 07/2015; 5:550-6. DOI:10.1016/j.fob.2015.06.009 · 1.52 Impact Factor
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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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    ABSTRACT: Long-lived post-mitotic cells, such as the majority of human neurons, must respond effectively to ongoing changes in neuronal stimulation or microenvironmental cues through transcriptional and epigenomic regulation of gene expression. The role of epigenomic regulation in neuronal function is of fundamental interest to the neuroscience community, as these types of studies have transformed our understanding of gene regulation in post-mitotic cells. This perspective article highlights many of the resources available to researchers interested in neuroepigenomic investigations and discusses some of the current obstacles and opportunities in neuroepigenomics.
    01/2015; 1:2-13. DOI:10.1016/j.nepig.2014.10.001
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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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