title: An epigenetic blockade of cognitive functions in the neurodegenerating brain.
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.
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Gräff
authors.forename: Damien
authors.initials: D
authors.lastname: Rei
authors.forename: Ji-Song
authors.initials: JS
authors.lastname: Guan
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Wang
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Seo
authors.forename: Krista M
authors.initials: KM
authors.lastname: Hennig
authors.forename: Thomas J F
authors.initials: TJ
authors.lastname: Nieland
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Fass
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Kao
authors.forename: Martin
authors.initials: M
authors.lastname: Kahn
authors.forename: Susan C
authors.initials: SC
authors.lastname: Su
authors.forename: Alireza
authors.initials: A
authors.lastname: Samiei
authors.forename: Nadine
authors.initials: N
authors.lastname: Joseph
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Ivana
authors.initials: I
authors.lastname: Delalle
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008569:Memory Disorders / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D019636:Neurodegenerative Diseases / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D010446:Peptide Fragments / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006657:Histones; D010446:Peptide Fragments; D011965:Receptors, Glucocorticoid; C075222:amyloid beta-protein (1-42); D006861:Hydrogen Peroxide; D012319:RNA Polymerase II; C533423:HDAC2 protein, human; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2