Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau

Jeong, Hyeanjeong; Shin, Sera; Lee, Jung Hoon; Lee, Soo Hyun; Baik, Ja Hyun; Lim, Sungsu; Kim, Yun Kyung

doi:10.3390/ijms20174283

Cited by 16 publications

(7 citation statements)

References 56 publications

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“…Acetylation of tau has been shown to cause inhbition of its degradation leading to accummultaion of tau. A careful evaluation of tau acetylation has been suggested during treatment with HDACi (Jeong et al, 2019).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

2020

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Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.

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Section: Alzheimer's Diseasementioning

confidence: 99%

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

2020

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“…1A). By using tau-BiFC cell model, we have characterized prion-like tau oligomers 19 , and investigated pathological tau modi cation [34][35][36] .…”

Section: Introductionmentioning

confidence: 99%

Levosimendan inhibits disulfide tau oligomerization ameliorating tau pathology in TauP301L-BiFC mice

Kim

Pae

Lim

et al. 2022

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Tau oligomers play critical roles in tau pathology, responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization becomes an important therapeutic strategy to treat tauopathies including Alzheimer’s disease. However, progress has been slow due to difficulties of detecting tau oligomers in cellular context. Toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened FDA-approved & Passed PhaseI drug library, and identified levosimendan as a potent anti-tau agent inhibiting tau oligomerization. 14C-isotope labeling of levosimendan identified that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan was able to disassemble tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents, methylene blue and LMTM, failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued tauopathy-induced cognitive declines in TauP301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.

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“…To date, research efforts have been largely directed to the use of HDAC inhibitors as potential anti-cancer agents [ 8 , 9 , 10 , 11 , 12 , 13 ]. Nevertheless, other applications such as anti-inflammatory [ 14 , 15 , 16 , 17 , 18 , 19 ], antifibriotic [ 20 , 21 , 22 , 23 , 24 ], or neuroprotective effect in Huntington’s disease [ 25 , 26 , 27 ], Alzheimer disease [ 27 , 28 ], spinal muscular atrophy [ 29 ], or Friedreich’s ataxia were studied [ 30 ]. HDAC inhibitors were postulated as possible therapeutic agents in asthma and chronic obstructive pulmonary disease (COPD) [ 31 ], methamphetamine addiction [ 32 ], heart failure [ 33 , 34 , 35 ], diabetes [ 36 , 37 ], depression [ 38 ], or suppression of aging processes [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues

et al. 2021

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Histone deacetylase (HDAC) inhibitors are a class of drugs used in the cancer treatment. Here, we developed a library of 19 analogues of Vorinostat, an HDAC inhibitor used in lymphomas treatment. In Vorinostat, we replaced the hydrophobic phenyl group with various tricyclic ‘caps’ possessing a central, eight-membered, heterocyclic ring, and investigated the HDAC activity and cytotoxic effect on the cancer and normal cell lines. We found that 3 out of the 19 compounds, based on dibenzo[b,f]azocin-6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one, and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds, showed better HDACs inhibition than the referenced Vorinostat. In leukemic cell line MV4-11 and in the lymphoma cell line Daudi, three compounds showed lower IC50 values than Vorinostat. These compounds had higher activity and selectivity against MV4-11 and Daudi cell lines than reference Vorinostat. We also observed a strong correlation between HDACs inhibition and the cytotoxic effect. Cell lines derived from solid tumours: A549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) as well as reference BALB/3T3 (normal murine fibroblasts) were less susceptible to compounds tested. Developed derivatives show improved properties than Vorinostat, thus they could be considered as possible agents for leukemia and lymphoma treatment.

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Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau

Cited by 16 publications

References 56 publications

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

Levosimendan inhibits disulfide tau oligomerization ameliorating tau pathology in TauP301L-BiFC mice

Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues

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