Celastrol, a TFEB (transcription factor EB) agonist, is a promising drug candidate for Alzheimer disease

Zhang, Wei1,2,3; Wang, Jigang1,2,4,5,6,7; Yang, Chuanbin1,2

2022-07-03

10.1080/15548627.2022.2046437

Autophagy   Impact Factor & Quartile

1554-8627

1554-8635

Alzheimer disease (AD) is the most common neurodegenerative disease. Unfortunately, current effective therapeutics for AD are limited and thus the discovery of novel anti-AD agents is urgently needed. A key pathological hallmark of AD is the accumulation of phosphorylated MAPT/tau (microtubule associated protein tau) aggregates to form neurofibrillary tangles. Autophagy is a conserved catabolic process that degrades protein aggregates or organelles via lysosomes. TFEB (transcription factor EB), a master regulator of autophagy, transcriptionally regulates multiple autophagy, and lysosomal-related genes. A compromised autophagy-lysosomal pathway (ALP) has been implicated in AD progression, and enhancing TFEB-mediated ALP to degrade MAPT/tau aggregates is a promising anti-AD strategy. In a recent study, we showed that celastrol, a natural small molecule with an anti-obesity effect, is a novel TFEB activator, which enhances autophagy and lysosomal biogenesis both in vitro and in animal brains. Consequently, celastrol promotes the degradation of phosphorylated MAPT/tau aggregates both in cells and in the brain of P301S MAPT/tau and 3XTg mice, two commonly used AD animal models. Interestingly, celastrol also alleviates memory deficits in these mice. Altogether, celastrol enhances TFEB-mediated autophagy and lysosomal biogenesis to ameliorate MAPT/tau pathology, suggesting that celastrol represents a novel anti-AD and other tauopathies drug candidate.

Alzheimer disease autophagy celastrol lysosome MTOR tau TFEB

SCI

English

Corresponding

National Natural Science Foundation of China[82003721] ; Shenzhen Science and Technology Innovation Commission["JCYJ20210324114014039","JCYJ20210324115800001"] ; China Postdoctoral Science Foundation[2020M683182] ; Guangdong Basic and Applied Basic Research Foundation[2020A1515110549] ; National Key Research and Development Program of China[2020YFA0908000] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-C-202002]

Cell Biology

Cell Biology

WOS:000765240700001

TAYLOR & FRANCIS INC

Web of Science

1.Jinan Univ, Dept Geriatr, Shenzhen Peoples Hosp, Clin Med Coll 2, Shenzhen 518020, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Guangdong, Peoples R China
3.Jinan Univ, Integrated Chinese & Western Med Postdoctoral Res, Guangzhou, Guangdong, Peoples R China
4.China Acad Chinese Med Sci, Artemisinin Res Ctr, Beijing, Peoples R China
5.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing, Peoples R China
6.Cent Peoples Hosp Zhanjiang, Zhanjiang, Guangdong, Peoples R China
7.Southern Med Univ, Dongguan Maternal & Child Hlth Care Hosp, Ctr Reprod Med, Dongguan, Guangdong, Peoples R China

Zhang, Wei,Wang, Jigang,Yang, Chuanbin. Celastrol, a TFEB (transcription factor EB) agonist, is a promising drug candidate for Alzheimer disease[J]. Autophagy,2022,18(7).

Zhang, Wei,Wang, Jigang,&Yang, Chuanbin.(2022).Celastrol, a TFEB (transcription factor EB) agonist, is a promising drug candidate for Alzheimer disease.Autophagy,18(7).

Zhang, Wei,et al."Celastrol, a TFEB (transcription factor EB) agonist, is a promising drug candidate for Alzheimer disease".Autophagy 18.7(2022).