Chlorogenic Acid Alleviates Aβ25-35-Induced Autophagy and Cognitive Impairment via the mTOR/TFEB Signaling Pathway

Lijuan Gao,1,2,* Xiaoqiong Li,1,2,* Shi Meng,1,2,* Tengyun Ma,1,2 Lihong Wan,3,* Shijun Xu1,2,* 1College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, People's Republic of China; 2Institute of Meterial Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, People's Republic of China; 3Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China*These authors contributed equally to this workCorrespondence: Shijun XuCollege of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, People's Republic of ChinaTel +86-28-61800231Fax +86-28-61800234Email xushijun@cdutcm.edu.cnLihong WanDepartment of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of ChinaTel/ Fax +86-28-85501278Email wanlihong1976@sina.comPurpose: Chlorogenic acid (CGA), a phenolic acid isolated from fruits and vegetables, has been established to have neuroprotective properties in relation to Alzheimer's disease (AD). However, the precise mechanism by which CGA prevents cognitive deficits in AD has not been well studied. This study aimed to explore the potential molecular mechanism of CGA action using an Aβ25-35-induced SH-SY5Y neuron injury and cogxnitive deficits model in APP/PS1 mice.Methods: Three-month-old male APP/PS1 double transgenic mice and a human neuroblastoma cell line (SH-SY5Y) were used to assess the effects of CGA on AD in vivo and in vitro, respectively. Cognitive function in mice was measured using a Morris water maze (MWM) test. Hematoxylin and eosin, monodansylcadaverine fluorescence, LysoTracker Red (LTR), and immunofluorescence staining were used to evaluate the morphological changes in vivo and in vitro. The protein expressions of autophagy markers (LC3B-II/LC3B-I, p62/SQSTM, beclin1 and Atg5) and lysosomal-function-related markers (cathepsin D, mTOR, p-mTOR P70S6K, p-p70s6k and TFEB) were analyzed with Western blot analyses.Results: CGA treatment significantly improved spatial memory, relieved neuron damage, and inhibited autophagy in APP/PS1 mice (P< 0.05). Moreover, CGA notably suppressed autophagosome production and enhanced autophagy flux in SH-SY5Y cells induced by Aβ25-35 (P< 0.05). Further analysis showed that CGA mar