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Updated: Aug 8, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming
Dayuan Wang1, Xiao Gu1, Xinyi Ma1
1Department 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.
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.
Insights
A natural compound, alpha-mangostin, rejuvenates brain immune cells (microglia) by reprogramming their metabolism. This enhances their ability to clear toxic protein aggregates, offering a potential universal therapy for neurodegenerative diseases like Alzheimer's and Parkinson's.
Area of Science:
- Neuroscience
- Immunology
- Metabolic pathways
Background:
- Microglial cells are crucial for clearing misfolded proteins (amyloid-beta, tau, alpha-synuclein) in neurodegenerative diseases.
- Current methods for removing these proteins are limited due to their complex structures and varied pathogenic forms.
- A universal therapeutic strategy for clearing diverse misfolded proteins is needed.
Purpose of the Study:
- To investigate the potential of alpha-mangostin in rejuvenating microglial surveillance capacity.
- To explore the metabolic reprogramming effects of alpha-mangostin on disease-associated microglia.
- To evaluate the therapeutic efficacy of nanoformulated alpha-mangostin in Alzheimer's and Parkinson's disease models.
Main Methods:
- Metabolic analysis of microglia treated with alpha-mangostin, focusing on shifts from glycolysis to oxidative phosphorylation.
- Assessment of microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins.
- In vivo studies using Alzheimer's disease and Parkinson's disease mouse models with nanoformulated alpha-mangostin.
Main Results:
- Alpha-mangostin reprogrammed microglial metabolism, shifting from glycolysis to oxidative phosphorylation.
- This metabolic shift rejuvenated microglial surveillance, enhancing phagocytosis and autophagy for clearing diverse misfolded proteins.
- Nanoformulated alpha-mangostin effectively delivered the compound to microglia, reducing their reactive state and improving clearance capacity.
- Treatment significantly alleviated neuropathological changes in both Alzheimer's and Parkinson's disease models.
Conclusions:
- Metabolic reprogramming of microglia offers a viable strategy for enhancing the clearance of multiple misfolded proteins.
- Nanoformulated alpha-mangostin demonstrates potential as a universal therapeutic agent for neurodegenerative diseases.
- This approach rejuvenates microglial surveillance, addressing key pathological hallmarks of diseases like Alzheimer's and Parkinson's.
