A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models

Ju Xian Song, Sandeep Malampati, Yu Zeng, Siva Sundara Kumar Durairajan, Chuan Bin Yang, Benjamin Chun Kit Tong, Ashok Iyaswamy, Wen Bin Shang, Sravan Gopalkrishnashetty Sreenivasmurthy, Zhou Zhu, King Ho Cheung, Jia Hong Lu, Chunzhi Tang, Nenggui Xu, Min Li

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy-lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta-amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg-AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C-terminal fragments (CTF-β/α), β-amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.

Original languageEnglish (US)
Article numbere13069
JournalAging cell
Volume19
Issue number2
DOIs
StatePublished - Feb 1 2020
Externally publishedYes

Keywords

  • Alzheimer's disease
  • MAPT/Tau
  • TFEB
  • beta-amyloid
  • curcumin analog C1

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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