https://scholars.lib.ntu.edu.tw/handle/123456789/565270
標題: | The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model article | 作者: | Fan S.-J. Huang F.-I. Liou J.-P. CHIA-RON YANG |
公開日期: | 2018 | 卷: | 9 | 期: | 6 | 起(迄)頁: | 655 | 來源出版物: | Cell Death and Disease | 摘要: | Alzheimer's disease (AD) is a dreadful neurodegenerative disease that leads to severe impairment of cognitive function, leading to a drastic decline in the quality of life. The primary pathological features of AD include senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs), comprising aggregated amyloid β (Aβ) and hyperphosphorylated tau protein, respectively, in the hippocampus of AD patients. Histone deacetylase 6 (HDAC6) is a key enzyme in this neurodegenerative disease, in particular, as it relates to tau hyperphosphorylation. This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-Tau Ser396 in response to MPT0G211 treatment. In AD in vivo models, MPT0G211 appeared to ameliorate learning and memory impairment in animals. Furthermore, MPT0G211 treatment reduced the amount of phosphorylated tau in the hippocampal CA1 region. In summary, MPT0G211 treatment appears to be a promising strategy for improving the AD phenotypes, including tau hyperphosphorylation and aggregation, neurodegeneration, and learning and memory impairment, making it a valuable agent for further investigation. ? 2018 The Author(s). |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85047873246&doi=10.1038%2fs41419-018-0688-5&partnerID=40&md5=1a8402ccc23f5f6d066ac540b5023cf8 https://scholars.lib.ntu.edu.tw/handle/123456789/565270 |
ISSN: | 20414889 | DOI: | 10.1038/s41419-018-0688-5 | SDG/關鍵字: | glycogen synthase kinase 3beta; heat shock protein 90; histone deacetylase 6; histone deacetylase inhibitor; memantine; mpt 0g 211; neuroprotective agent; protein kinase B; ricolinostat; serine; tau protein; unclassified drug; benzamide derivative; glycogen synthase kinase 3beta; histone deacetylase inhibitor; neuroprotective agent; proteasome; protein aggregate; quinoline derivative; tau protein; Alzheimer disease; animal cell; animal experiment; animal model; Article; blood brain barrier; cognitive defect; controlled study; down regulation; elevated plus maze test; enzyme binding; enzyme inhibition; escape latency; female; hippocampal CA1 region; human; human cell; in vivo study; learning disorder; memory disorder; Morris water maze test; mouse; Neuro-2a cell line; neurofibrillary tangle; neuroprotection; nonhuman; priority journal; protein acetylation; protein aggregation; protein binding; protein phosphorylation; SH-SY5Y cell line; spatial memory; treatment response; ubiquitination; upregulation; Alzheimer disease; animal; apoptosis; biological model; blood; chemistry; cognitive defect; complication; disease model; drug effect; metabolism; phosphorylation; protein degradation; Sprague Dawley rat; tumor cell line; Alzheimer Disease; Animals; Apoptosis; Benzamides; Cell Line, Tumor; Cognition Disorders; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Histone Deacetylase Inhibitors; Memory Disorders; Models, Biological; Neuroprotective Agents; Phosphorylation; Proteasome Endopeptidase Complex; Protein Aggregates; Proteolysis; Quinolines; Rats, Sprague-Dawley; tau Proteins; Ubiquitination |
顯示於: | 藥學系 |
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