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.
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)。
作者简介
Corresponding authors:Xiaoling Gao.Tel./fax:+862164674721.E-mail addresses:shellygaol@sjtu.edu.cn(Xiaoling Gao);Corresponding authors:Hongzhuan Chen.E-mail addresses:yaoli@shsmu.edu.cn(Hongzhuan Chen)Tel./fax:+862163846590776580。
