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Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition.

ABSTRACT: INTRODUCTION: Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. METHODS: We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). RESULTS: We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically. CONCLUSION: Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology.

SUBMITTER: Selenica ML

PROVIDER: S-EPMC3978441 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition.

Selenica Maj-Linda ML Benner Leif L Housley Steven B SB Manchec Barbara B Lee Daniel C DC Nash Kevin R KR Kalin Jay J Bergman Joel A JA Kozikowski Alan A Gordon Marcia N MN Morgan Dave D

Alzheimer's research & therapy 20140227 1

<h4>Introduction</h4>Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of t ...[more]

PMID: 24576665

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Project description:Introduction: Obesity and overweight affect more than one third of the world population, and are significant risk factors for type II diabetes, cardiovascular disease and cancer. Common obesity is usually accompanied by hyperleptinemia and leptin resistance. Purpose: Here, we investigate the molecular pathways underlying the effects of HDAC6 inhibition in reversing diet-induced obesity and interrogate potential pathways that link HDAC6 with leptin receptor signaling by conducting whole transcriptome analysis in white adipose tissues of the diet-induced obese mice that were treated with tubastatin A (an HDAC6-specific inhibitor) and in fat-specific HDAC6 knockout mice. Methods: Male 4-5 week-old C57B/6J wild type mice were fed with high fat diet for 16-20 weeks to generate diet-induced obese (DIO) mice. Around 28 weeks of age, mice were treated with daily ip injections of either tubastatin A-HCl (TubA, 25 mg/kg) or vehicle for four days. We probed the whole transcriptome in epididymal white adipose tissue (eWAT), and inguinal white adipose tissue (iWAT) following vehicle or TubA administration (eWAT.Veh, eWAT.TubA, iWAT.Veh, iWAT.TubA groups). In a separate cohort, DIO HDAC6 global knockout mice were treated with vehicle (Veh group) or TubA (TubA group). eWAT was excised for RNA extraction. In the third cohort, adipose tissue specific HDAC6 knockout mice were generated crossing adiponectin-Cre mice with HDAC6-floxed mice. These fat specific HDAC6 KO mice (AdKO) and their adiponectin-Cre controls (AdCre) were treated with vehicle for five weeks. eWAT was excised for RNA extraction.Total RNA samples from each tissue were extracted using Trizol. RNA Sequencing for the wild-type iWAT and eWAT samples from vehicle or TubA-treated mice was performed by the University of Michigan Sequencing Core, using the Illumina Hi-Seq 4000 platform. RNA sequencing for the other samples were conducted by Novogene, NovaSeq 6000 PE150, HiSeq SE50 platform. The following bioinformatics analysis have been conducted by Novogene: 1. Data Quality Control: filtering reads containing adapter or with low quality. 2. Statistics Analysis of Data Production and Quality. 3. Mapping Reads to Reference Genome. 4. Gene Expression Quantification. 5. Correlation analysis (For biological replicates only). 6. Differential Expression Analysis (two or more groups of samples). 7. GO Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples). 8. KEGG Pathway Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples). 9. GSEA Enrichment Analysis of Expressed Genes (two or more groups of samples). 10. Protein Protein Interaction Analysis. 11. Reactome Pathway Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples and only for mouse samples). 12. Oncogene Functional Annotation analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples and only for mouse sample). Results: Inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent anti-obesity agents, and leptin sensitizers. HDAC6 inhibitor TubA suppresses food intake and reduce obesity, in an HDAC6-dependent manner, resulting in up to fifty percent decrease in fat mass in DIO mice accompanied by significantly reduced hepatic steatosis and improved systemic glucose homeostasis. Conclusions: Mechanistically, peripheral -but not central- inhibition of HDAC6 confers central leptin sensitivity, and the anti-obesity effect of TubA is significantly attenuated in animals defective in the central leptin-melanocortin circuitry, including the db/db and MCR4 KO mice.

Dataset Information

Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition.

Publications

Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition.

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