Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming.

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

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Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming.

Author: Dayuan WANG ¹ ; Xiao GU ¹ ; Xinyi MA ¹ ; Jun CHEN ² ; Qizhi ZHANG ² ; Zhihua YU ¹ ; Juan LI ¹ ; Meng HU ¹ ; Xiaofang TAN ¹ ; Yuyun TANG ¹ ; Jianrong XU ¹ ; Minjun XU ² ; Qingxiang SONG ¹ ; Huahua SONG ¹ ; Gan JIANG ¹ ; Zaiming TANG ³ ; Xiaoling GAO ¹ ; Hongzhuan CHEN ¹
Author Information

1. Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
2. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
3. Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Publication Type:Journal Article
Keywords: Degradation; Metabolism; Microglia; Misfolded proteins; Nanoparticles; Neurodegenerative diseases; Phagocytosis; Polyphenol
From: Acta Pharmaceutica Sinica B 2023;13(2):834-851
CountryChina
Language:English
Abstract: Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α-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 of α-mangostin efficiently delivered α-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 nanoformulated α-mangostin as a potential and universal therapy against neurodegenerative diseases.