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  HDAC inhibitor-dependent transcriptome and memory reinstatement in cognitive decline models.

Benito, E., Urbanke, H., Ramachandran, B., Barth, J., Halder, R., Awasthi, A., et al. (2015). HDAC inhibitor-dependent transcriptome and memory reinstatement in cognitive decline models. Journal of Clinical Investigation, 125(9), 3572-3584. doi:10.1172/JCI79942.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-4347-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-B95B-2
Genre: Journal Article

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 Creators:
Benito, E., Author
Urbanke, H., Author
Ramachandran, B., Author
Barth, J., Author
Halder, R., Author
Awasthi, A., Author
Jain, G., Author
Capece, J. G., Author
Burkhardt, S., Author
Navarro-Sala, M., Author
Nagarajan, S., Author
Schütz, A. L., Author
Johnsen, S. A., Author
Bonn, S., Author
Lührmann, R.1, Author              
Dean, C., Author
Fischer, A., Author
Affiliations:
1Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              

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 Abstract: Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's disease (AD). Effective therapies for these diseases are lacking. Here, we evaluated mouse models of age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity in the brain and peripheral organs. We determined that aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region as the result of epigenetic-dependent alterations in gene expression. In both amyloid and aging models, inflammation was associated with increased gene expression linked to a subset of transcription factors, while plasticity gene deregulation was differentially mediated. Amyloid pathology impaired histone acetylation and decreased expression of plasticity genes, while aging altered H4K12 acetylation-linked differential splicing at the intron-exon junction in neurons, but not nonneuronal cells. Furthermore, oral administration of the clinically approved histone deacetylase inhibitor vorinostat not only restored spatial memory, but also exerted antiinflammatory action and reinstated epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This study provides a systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and suggests that histone deacetylase inhibitors should be further explored as a cost-effective therapeutic strategy against age-associated cognitive decline.

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Language(s): eng - English
 Dates: 2015-08-172015-09-01
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1172/JCI79942
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Title: Journal of Clinical Investigation
Source Genre: Journal
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Pages: - Volume / Issue: 125 (9) Sequence Number: - Start / End Page: 3572 - 3584 Identifier: -