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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    • "We mapped the human ASD candidates onto their unambiguous one-to-one mouse orthologs (341 of 378 ASD candidate genes mapped) and observed that these ASD candidate orthologs displayed significant downregulation in the mouse brain at E14.5 when both Hdac1 and Hdac2 were knocked out (p = 2.4e-7, Wilcoxon rank-sum test, relative to mouse genes with one-to-one human orthologs; Figure 3A). Since HDAC2 is implicated in ALZ (Grä ff et al., 2012), we further examined whether the above downregulation was specific for ASD. We analyzed genes implicated in intellectual disability (ID, 401 genes), SZ (499 genes), and ALZ (613 genes) (Supplemental Experimental Procedures). "

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    • "shown to bind BDNF promoters I, II and IV (Gräff et al., 2012; Guan et al., 2009), the role of individual class I HDAC isoforms, in relation to BDNF, is still unknown. "
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