An epigenetic blockade of cognitive functions in the neurodegenerating brain

• Published in: Nature (London) Vol. 483; no. 7388; pp. 222 - 226
• Main Authors: Gräff, Johannes, Rei, Damien, Guan, Ji-Song, Wang, Wen-Yuan, Seo, Jinsoo, Hennig, Krista M., Nieland, Thomas J. F., Fass, Daniel M., Kao, Patricia F., Kahn, Martin, Su, Susan C., Samiei, Alireza, Joseph, Nadine, Haggarty, Stephen J., Delalle, Ivana, Tsai, Li-Huei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.03.2012; Nature Publishing Group
• Subjects: 631/378/2584; 631/378/2591; 631/378/2649; 692/699/375/365; Acetylation - drug effects; Adult and adolescent clinical studies; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - toxicity; Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Causes of; Cognition disorders; Cognitive ability; Cyclin-dependent kinases; Degeneration; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Epigenesis, Genetic - drug effects; Epigenetic inheritance; Epigenetics; Gene Expression Regulation - drug effects; Gene Knockdown Techniques; Genetic aspects; Genetics; Health aspects; Hippocampus - drug effects; Hippocampus - metabolism; Histone Deacetylase 2 - deficiency; Histone Deacetylase 2 - genetics; Histone Deacetylase 2 - metabolism; Histones - metabolism; Humanities and Social Sciences; Humans; Hydrogen Peroxide - toxicity; Kinases; letter; Medical sciences; Memory Disorders - complications; Memory Disorders - genetics; Memory Disorders - physiopathology; Mice; multidisciplinary; Nervous system; Neurodegeneration; Neurodegenerative Diseases - complications; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - physiopathology; Neurology; Neuronal Plasticity - drug effects; Neuronal Plasticity - genetics; Organic mental disorders. Neuropsychology; Peptide Fragments - toxicity; Phosphorylation - drug effects; Plasticity; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Glucocorticoid - metabolism; RNA polymerase; RNA Polymerase II - metabolism; Science; Science (multidisciplinary); United States; Nervous system diseases; Cognitive disorder; Alzheimer disease; Pathogenesis; Central nervous system disease; Degenerative disease; Genetic determinism; Cerebral disorder
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature10849

Histone deacetylase 2 is shown to suppress genes involved in cognitive function epigenetically, potentially opening the door to treatments for Alzheimer’s and other neurodegenerative diseases by developing HDAC2-selective inhibitors. Blocking cognitive decline What causes the cognitive decline associated with neurodegenerative diseases is not fully understood. This study reveals a novel epigenetic mechanism by which Alzheimer's-disease-related neurotoxicity reduces the expression of genes necessary for neural plasticity. In two mouse models of Alzheimer's disease — and in post-mortem samples from human subjects — expression of the epigenetic regulator histone deacetylase 2 (HDAC2) is elevated. Reversing the upregulation of HDAC2 by short-hairpin-RNA-mediated knockdown in mice restores the expression of HDAC2 target genes and abolishes the neurodegeneration-associated memory impairment. Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease 1 . The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge 2 . 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.