Open AccessA small molecule transcription factor EB activator ameliorates beta‐amyloid precursor protein and Tau pathology in Alzheimer's disease models
Author(s) -
Song JuXian,
Malampati Sandeep,
Zeng Yu,
Durairajan Siva Sundara Kumar,
Yang ChuanBin,
Tong Benjamin ChunKit,
Iyaswamy Ashok,
Shang WenBin,
Sreenivasmurthy Sravan Gopalkrishnashetty,
Zhu Zhou,
Cheung KingHo,
Lu JiaHong,
Tang Chunzhi,
Xu Nenggui,
Li Min
Publication year - 2020
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13069
Subject(s) - tfeb , autophagy , curcumin , activator (genetics) , tauopathy , biology , basic helix loop helix leucine zipper transcription factors , microbiology and biotechnology , amyloid precursor protein , presenilin , transcription factor , alzheimer's disease , neuroscience , biochemistry , medicine , neurodegeneration , disease , dna binding protein , gene , apoptosis
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.