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.
Highlights
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease which causes dementia in the elderly
Exogenous transcription factor EB (TFEB) expression mediated by AAV injection in hippocampal astrocytes and neurons of amyloid precursor protein (APP)/PS1 mice reportedly promotes the degradation of APP and APP C-terminal fragments (CTFs) and reduces β-amyloid peptides (Aβ) generation (Xiao et al, 2014, 2015)
Accumulating evidence has suggested that targeting TFEB to regulate autophagy–lysosome pathway (ALP) is a promising approach to developing new drugs to treat neurodegenerative disorders including AD (Chandra, Jana, & Pahan, 2018; Chauhan et al, 2015; Martini-Stoica et al, 2018; Polito et al, 2014; Wang et al, 2016; Xiao et al, 2014, 2015)
Summary
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease which causes dementia in the elderly. Curcumin, but not C1, significantly inhibited MTORC1 activity evidenced by the decrease in p-MTOR and its substrate p-RPS6KB1 in the brains of 5xFAD mice (Figure S2C,D) These results indicate that curcumin can reduce APP and Aβ at a relatively high dose, its effect may be mainly mediated by MTORC1 inhibition or BACE1 inhibition as reported previously (Zheng et al, 2017). The concentration of C1 was 216.7 ± 55.3 ng/g (equivalent to 0.74 ± 0.19 μM) and 261.2 ± 32.9 ng/g (equivalent to 0.89 ± 0.11 μM) in male (n = 5) and female (n = 5) mice, respectively (Figure S2E) Together, these results indicate that C1 promotes the degradation of APP fragments and reduces Aβ by promoting TFEB-mediated autophagy and lysosomal biogenesis in the brains of 5xFAD mice.
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