HDAC inhibitor-dependent transcriptome and memory reinstatement in cognitive decline models
| Autor: | Magdalena Navarro-Sala, Anna-Lena Schütz, Vincenzo Capece, Camin Dean, Eva Benito, Gaurav Jain, Hendrik Urbanke, Sankari Nagarajan, Susanne Burkhardt, Stefan Bonn, Reinhardt Lührmann, Rashi Halder, Andre Fischer, Jonas Barth, Binu Ramachandran, Steven A. Johnsen, Ankit Awasthi |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Aging
genetics [Amyloid] metabolism [Histones] genetics [Transcriptome] genetics [Alzheimer Disease] Bioinformatics Hydroxamic Acids Transcriptome Histones pathology [Alzheimer Disease] Mice drug therapy [Alzheimer Disease] metabolism [Transcription Factors] Cognitive decline Histone deacetylase 5 Vorinostat Histone deacetylase inhibitor Acetylation General Medicine pathology [CA1 Region Hippocampal] genetics [Transcription Factors] enzymology [CA1 Region Hippocampal] genetics [Histones] drug effects [Transcriptome] Alzheimer's disease pharmacology [Hydroxamic Acids] Research Article medicine.drug Amyloid medicine.drug_class Biology drug effects [Memory] Alzheimer Disease Memory medicine Animals Humans ddc:610 CA1 Region Hippocampal metabolism [Amyloid] enzymology [Alzheimer Disease] Epigenome medicine.disease Histone Deacetylase Inhibitors Disease Models Animal Histone deacetylase drug effects [Acetylation] Neuroscience pharmacology [Histone Deacetylase Inhibitors] Transcription Factors |
| Zdroj: | The journal of clinical investigation 125(9), 3572-3584 (2015). doi:10.1172/JCI79942 Journal of Clinical Investigation |
| DOI: | 10.1172/JCI79942 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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