期刊
MOLECULAR AND CELLULAR NEUROSCIENCE
卷 95, 期 -, 页码 13-24出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2018.12.007
关键词
Alzheimer's disease; Okadaic acid; Transcription factor EB; Tau; Ouabain; mTOR
资金
- National Research Foundation of Korea (NRF) - Ministry of Education [2015H1A2A1034992]
- NRF - Ministry of Science, ICT and Future Planning [2018R1A2A1A05077403, 2017R1A2B2010901]
- Asan Institute for Life Sciences, Seoul, Korea [2013-7204]
- National Research Foundation of Korea [2015H1A2A1034992, 2018R1A2A1A05077403, 2017R1A2B2010901] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The number of neurofibrillary tangles containing abnormal hyperphosphorylated tau protein correlates with the degree of dementia in Alzheimer's disease (AD). In addition, autophagosome accumulation and disturbance of autophagy, the process by which toxic aggregate proteins are degraded in the cytosol, are also found in AD models. These indicate that regulation of the autophagy-lysosome system may be a potential therapeutic target for AD. Activation of transcription factor EB (TFEB), a master regulator of autophagy-lysosome system gene transcription, reduces the amount of tau in APP mice. Here, to identify potential therapeutic compounds for AD, we performed two types of screening to determine pharmacologically active compounds that increase 1) neuronal viability in okadaic acid-induced tau hyperphosphorylation-related neurodegeneration models and 2) nuclear localization of TFEB in high-contents screening. Ouabain, a cardiac glycoside, was discovered as a common hit compound in both screenings. It also exhibited a significant protective effect in tau transgenic fly and mouse models in vivo. This work demonstrates that ouabain enhances activation of TFEB through inhibition of the mTOR pathway and induces downstream autophagy-lysosomal gene expression and cellular restorative properties. Therefore, therapeutic approaches using ouabain reduce the accumulation of abnormal toxic tau in vitro and in vivo.
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