Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming

Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and a-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, a-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 a-mangostin efficiently delivered a-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 a-mangostin as a potential and uni-versal therapy against neurodegenerative diseases.2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

The polyphenol compound a-mangostin can reactivate the immune function of disease-associated microglia by reprogramming their metabolism, enhancing the degradation and phagocytosis of various misfolded proteins. Nanoformulated a-mangostin efficiently delivers the compound to microglia, relieving their reactive status and improving neuropathological changes in Alzheimer's and Parkinson's disease model mice. These findings provide evidence for rejuvenating microglial surveillance and suggest nanoformulated a-mangostin as a potential universal therapy for neurodegenerative diseases.