mTOR-Mediated Immunometabolic Reprogramming Nanomodulators Enable Sensitive Switching of Energy Deprivation-Induced Microglial Polarization for Alzheimer's Disease Management.

Abstract	Metabolic reprogramming that senses brain homeostasis imbalances is necessary to drive detrimental microglial polarization, and specific targeting of this process contributes to the flexible control of pathological inflammatory responses in Alzheimer's disease (AD), displaying distinctive therapeutic benefits. Herein, glutathione-functionalized gold nanocages loaded with the immunosuppressant fingolimod hydrochloride are developed as brain-targeted and microglia-located immunometabolic reprogramming nanomodulators (GAF NPs) for AD management. By virtue of glutathione-mediated transport properties, this nanomodulator can cross the blood-brain barrier and localize to microglia in AD lesions. Through blocking Akt/mTOR/HIF-1α signaling pathways, GAF NPs not only promote the dominated metabolic shift from glycolysis to oxidative phosphorylation under immune activation but also inhibit transporter-mediated glucose overconsumption by microglia. Correlation analysis based on real-time bioenergetic assessment and 18F-labeled fluorodeoxyglucose (FDG) PET reveals that brain glucose utilization and metabolism restored by GAF NP treatment can serve as a sensitive and effective indicator for microglial M1 to M2 polarization switching, ultimately alleviating neuroinflammation and its derived neurodegeneration as well as ameliorating cognitive decline in AD mice. This work highlights a potential nanomedicine aimed at modifying mTOR-mediated immunometabolic reprogramming to halt energy deprivation-induced AD progression.
Authors	Fan Yang, Dongju Zhao, Meng Cheng, Yining Liu, Ziyao Chen, Jin Chang, Yan Dou
Journal	ACS nano (ACS Nano) Vol. 17 Issue 16 Pg. 15724-15741 (08 22 2023) ISSN: 1936-086X [Electronic] United States
PMID	37565731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	TOR Serine-Threonine Kinases Glucose
Topics	Mice Animals Microglia (metabolism, pathology) Alzheimer Disease (drug therapy, pathology) TOR Serine-Threonine Kinases (metabolism, pharmacology) Signal Transduction Glucose (metabolism)

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