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, Hu Meng, Xiaofang Tan, Yuyun Tang, Jianrong Xu, Minjun Xu, Qingxiang Song, Huahua Song, Gan Jiang, Zaiming Tang, Xiaoling Gao, Hongzhuan Chen
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.