The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model article

Sheng Jun Fan, Fang I. Huang, Jing Ping Liou, Chia Ron Yang

研究成果: 雜誌貢獻文章

17 引文 斯高帕斯(Scopus)

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.
原文英語
文章編號655
期刊Cell Death and Disease
9
發行號6
DOIs
出版狀態已發佈 - 六月 1 2018

    指紋

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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