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.
ABSTRACT
Pharmacological activities of the effective constituents: essential oils, flavonoids andalkaloids, in fruit of Citrus aurantium L. were compared. Blood pressure was increased markedly by transfusion of the alkaloids. Contractions of isolated intestines were iuhibited byflavonoids. Essential oils significantly decreased the rate and frequency of writhing syndromeinduced by ip acetie acid and spontaneous locomotor activities in the mice with the exceptionfexciting at first followed by inhibiting the isolated intestines,which displayed analgesia andoceutral inhibition to a certain extent.