TY - JOUR
T1 - Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology
T2 - Implications for Alzheimer's disease therapy
AU - Yang, Chuanbin
AU - Su, Chengfu
AU - Iyaswamy, Ashok
AU - Krishnamoorthi, Senthil Kumar
AU - Zhu, Zhou
AU - Yang, Sichang
AU - Tong, Benjamin Chunkit
AU - Liu, Jia
AU - Sreenivasmurthy, Sravan G.
AU - Guan, Xinjie
AU - Kan, Yuxuan
AU - Wu, Aston Jiaxi
AU - Huang, Alexis Shiying
AU - Tan, Jieqiong
AU - Cheung, Kingho
AU - Song, Juxian
AU - Li, Min
N1 - Publisher Copyright:
© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences
PY - 2022/4
Y1 - 2022/4
N2 - Alzheimer's disease (AD), characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates, is the most common neurodegenerative disorder with limited therapeutic agents. Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates, and transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Thus, small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy. Here, we found that celastrol, an active ingredient isolated from the root extracts of Tripterygium wilfordii (Lei Gong Teng in Chinese) enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains. Importantly, celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice, two commonly used AD animal models. Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol. Overall, our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models. Therefore, Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.
AB - Alzheimer's disease (AD), characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates, is the most common neurodegenerative disorder with limited therapeutic agents. Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates, and transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Thus, small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy. Here, we found that celastrol, an active ingredient isolated from the root extracts of Tripterygium wilfordii (Lei Gong Teng in Chinese) enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains. Importantly, celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice, two commonly used AD animal models. Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol. Overall, our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models. Therefore, Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.
KW - Alzheimer's disease (AD)
KW - Autophagy
KW - Celastrol
KW - Lysosome biogenesis
KW - TFEB
KW - Tau
KW - Therapeutic target
KW - mTOR
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UR - http://www.scopus.com/inward/citedby.url?scp=85126053546&partnerID=8YFLogxK
U2 - 10.1016/j.apsb.2022.01.017
DO - 10.1016/j.apsb.2022.01.017
M3 - Article
C2 - 35847498
AN - SCOPUS:85126053546
SN - 2211-3835
VL - 12
SP - 1707
EP - 1722
JO - Acta Pharmaceutica Sinica B
JF - Acta Pharmaceutica Sinica B
IS - 4
ER -