한빛사 논문
Yoon Sun Chun1,6, Mi-Yeon Kim1,6, Sun-Young Lee1, Mi Jeong Kim1, Tae-Joon Hong1, Jae Kyong Jeon2, Dulguun Ganbat2, Hyoung Tae Kim1, Sang Seong Kim2,5, Tae-In Kam3,4,7,* and Sungho Han1,7,*
1Genuv Inc., Seoul 04520, Republic of Korea. 2College of Pharmacy, Hanyang University ERICA, Gyeonggi-do 15588, Republic of Korea. 3Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 4Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 5Present address: Department of photonics and nanoelectronics, Hanyang University ERICA, Gyeonggi-do 15588, Republic of Korea. 6These authors contributed equally: Yoon Sun Chun, Mi-Yeon Kim. 7These authors contributed equally: Tae-In Kam, Sungho Han.
*Corresponding author.
Abstract
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder, which is characterized by cognitive deficit due to synaptic loss and neuronal death. Extracellular amyloid β plaques are one of the pathological hallmarks of AD. The autophagic lysosomal pathway is the essential mechanism to maintain cellular homeostasis by driving clearance of protein aggregates and is dysfunctional in AD. Here, we showed that inhibiting MEK/ERK signaling using a clinically available MEK1/2 inhibitor, trametinib (GSK1120212, SNR1611), induces the protection of neurons through autophagic lysosomal activation mediated by transcription factor EB (TFEB) in a model of AD. Orally administered trametinib recovered impaired neural structures, cognitive functions, and hippocampal long-term potentiation (LTP) in 5XFAD mice. Trametinib also reduced Aβ deposition via induction of autophagic lysosomal activation. RNA-sequencing analysis revealed upregulation of autophagic lysosomal genes by trametinib administration. In addition, trametinib inhibited TFEB phosphorylation at Ser142 and promoted its nuclear translocation, which in turn induced autophagic lysosomal related genes, indicating that trametinib activates the autophagic lysosomal process through TFEB activation. From these observations, we concluded that MEK inhibition provides neuronal protection from the Aβ burden by increasing autophagic lysosomal activity. Thus, MEK inhibition may be an effective therapeutic strategy for AD.
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