Publication Date:
2012-03-06
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498952/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498952/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Graff, 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 -- R01 DA028301/DA/NIDA NIH HHS/ -- R01 MH095088/MH/NIMH NIH HHS/ -- R01 NS078839/NS/NINDS NIH HHS/ -- R01DA028301/DA/NIDA NIH HHS/ -- R01NS078839/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 29;483(7388):222-6. doi: 10.1038/nature10849.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22388814" target="_blank"〉PubMed〈/a〉
Keywords:
Acetylation/drug effects
;
Alzheimer Disease/complications/genetics/physiopathology
;
Amyloid beta-Peptides/toxicity
;
Animals
;
Brain/drug effects/metabolism/*physiopathology
;
Disease Models, Animal
;
*Epigenesis, Genetic/drug effects
;
Gene Expression Regulation/drug effects
;
Gene Knockdown Techniques
;
Hippocampus/drug effects/metabolism
;
Histone Deacetylase 2/deficiency/*genetics/metabolism
;
Histones/metabolism
;
Humans
;
Hydrogen Peroxide/toxicity
;
Memory Disorders/complications/*genetics/*physiopathology
;
Mice
;
Neurodegenerative Diseases/complications/*genetics/*physiopathology
;
Neuronal Plasticity/drug effects/genetics
;
Peptide Fragments/toxicity
;
Phosphorylation/drug effects
;
Promoter Regions, Genetic/drug effects/genetics
;
RNA Polymerase II/metabolism
;
Receptors, Glucocorticoid/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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