Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming

作     者：Dayuan Wang Xiao Gu Xinyi Ma Jun Chen Qizhi Zhang Zhihua Yu Juan Li Meng Hu Xiaofang Tan Yuyun Tang Jianrong Xu Minjun Xu Qingxiang Song Huahua Song Gan Jiang Zaiming Tang Xiaoling Gao Hongzhuan Chen Dayuan Wang;Xiao Gu;Xinyi Ma;Jun Chen;Qizhi Zhang;Zhihua Yu;Juan Li;Meng Hu;Xiaofang Tan;Yuyun Tang;Jianrong Xu;Minjun Xu;Qingxiang Song;Huahua Song;Gan Jiang;Zaiming Tang;Xiaoling Gao;Hongzhuan Chen

作者机构：Department of Pharmacology and Chemical BiologyState Key Laboratory of Oncogenes and Related GenesShanghai Universities Collaborative Innovation Center for Translational MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Key Laboratory of Smart Drug DeliveryMinistry of EducationSchool of PharmacyFudan UniversityShanghai 201203China Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai201203China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第2期

页      面：834-851页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100204[医学-神经病学] 10[医学] 

基　　金：supported by National Natural Science Foundation of China(Nos.81722043,92068111,81973272,82073836,81903582,China) granted from Shanghai Science and Technology Committee(19410710100,121XD1422200,China)。 

主　　题：Microglia Metabolism Misfolded proteins Phagocytosis Degradation Polyphenol Nanoparticles Neurodegenerative diseases 

摘      要：Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta,tau,andα-synuclein aggregates in neurodegenerative diseases.However,due to the complex structure and ambiguous pathogenic species of the misfolded proteins,a universal approach to remove the misfolded proteins remains unavailable.Here,we found that a polyphenol,α-mangostin,reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation,which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins.Nanoformulation ofα-mangostin efficiently deliveredα-mangostin to microglia,relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia,which thus impressively relieved the neuropathological changes in both Alzheimer’s disease and Parkinson’s disease model mice.These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming,and demonstrate nanoformulatedα-mangostin as a potential and universal therapy against neurodegenerative diseases.