Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer?s disease therapy

Yang, Chuanbin1,2; Su, Chengfu1,3,4; Iyaswamy, Ashok1,3; Krishnamoorthi, Senthil Kumar1; Zhu, Zhou1,3; Yang, Sichang1; Tong, Benjamin Chunkit1,3; Liu, Jia1,3; Sreenivasmurthy, Sravan G.1,3; Guan, Xinjie1; Kan, Yuxuan1; Wu, Aston Jiaxi1; Huang, Alexis Shiying1; Tan, Jieqiong5,6; Cheung, Kingho1,3; Song, Juxian1,7; Li, Min1,3

2022-04-01

10.1016/j.apsb.2022.01.0172211-3835

Acta Pharmaceutica Sinica B   Impact Factor & Quartile

2211-3835

2211-3843

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. @ 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

TFEB Autophagy Lysosome biogenesis Alzheimer?s disease (AD) Tau Celastrol mTOR Therapeutic target

SCI

English

Corresponding

Hong Kong Baptist University (China)[HKBU/RC-IRCs/17-18/03] ; Hong Kong General Research Fund (China)["GRF/HKBU12101417","GRF/HKBU12100618"] ; National Natural Science Foundation of China[81703487,81773926] ; Shenzhen Science and Technology Innovation Commission (China)["JCYJ20180302174028790","JCYJ20180507184656626","JCYJ20210324114014039"] ; Hong Kong Health and Medical Research Fund (China)["HMRF17182541","HMRF17182551"]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000808125600013

INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES

Web of Science

1.Hong Kong Baptist Univ, Mr & Mrs Ko Chi Ming Ctr Parkinsons Dis Res, Sch Chinese Med, Hong Kong, Peoples R China
2.Southern Univ Sci & Technol, Jinan Univ,Affiliated Hosp 1, Shenzhen Peoples Hosp, Dept Geriatr,Clin Med Coll 2, Shenzhen 518020, Peoples R China
3.Hong Kong Baptist Univ, Inst Res & Continuing Educ, Shenzhen 518057, Peoples R China
4.Henan Univ Chinese Med, Coll Pharm, Zhengzhou 450000, Peoples R China
5.Cent South Univ, Ctr Med Genet, Changsha 410078, Peoples R China
6.Cent South Univ, Hunan Key Lab Anim Model Human Dis, Sch Life Sci, Changsha 410078, Peoples R China
7.Guangzhou Univ Chinese Med, Med Coll Acupuncture Moxibust & Rehabil, Guangzhou 510632, Peoples R China

Yang, Chuanbin,Su, Chengfu,Iyaswamy, Ashok,et al. Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer?s disease therapy[J]. Acta Pharmaceutica Sinica B,2022,12(4).

Yang, Chuanbin.,Su, Chengfu.,Iyaswamy, Ashok.,Krishnamoorthi, Senthil Kumar.,Zhu, Zhou.,...&Li, Min.(2022).Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer?s disease therapy.Acta Pharmaceutica Sinica B,12(4).

Yang, Chuanbin,et al."Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer?s disease therapy".Acta Pharmaceutica Sinica B 12.4(2022).