An epigenetic blockade of cognitive functions in the neurodegenerating brain

By Johannes Gräff, Damien Rei, J. Guan, Wenyuan Wang, Jinsoo Seo, K. Hennig, T. J. Nieland, D. Fass, P. Kao, Martin Kahn and 6 more. Nature, 2012

848 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/8b47f6967b4dd8b58647688d2c93e4797afbe80c

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In Molecular Biology

1. Minoru Yoshida
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1. E. Seto
2. Huaxi Xu

Citations in the corpus

• Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “HDAC2 overexpression reduces dendritic spine density, and impairs synaptic plasticity and memory by blocking expression of genes related to neuroplasticity, whereas downregulation or inhibition of HDACs has been proven successful in restoring synaptic and cognitive function in AD animal models [508,”
• Erasers of histone acetylation: the histone deacetylase enzymes. (2014, background): “Conversely, Hdac2 deficiency results in increased synapse number and memory facilitation similar to chronic treatment with HDAC inhibitors in mice (e.g., Graff et al. 2012).”
• β-Hydroxybutyrate (2017, neutral): “HDAC2 expression is increased in the brains of two mouse dementia models as well as the brains of humans with Alzheimer’s disease (39).”
• The world of protein acetylation. (2016, background): “Naa10 interacts with the cytoplasmic domain of the β-amyloid precursor protein (APP), a protein that is processed to the amyloid β-protein (Aβ), which is the main component of amyloid plaques contributing to the development of Alzheimer's.”