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

被引：18

作者：

Yang, Fan ^{[1
,2
,3
]}

Zhao, Dongju ^{[1
]}

Cheng, Meng ^{[2
,3
]}

Liu, Yining ^{[1
]}

Chen, Ziyao ^{[1
]}

Chang, Jin ^{[1
]}

Dou, Yan ^{[2
,3
]}

机构：

[1] Tianjin Univ, Sch Life Sci, Tianjin 300072, Peoples R China

[2] Tianjin Med Univ Gen Hosp, Dept Radiol, Tianjin 300052, Peoples R China

[3] Tianjin Med Univ Gen Hosp, Tianjin Key Lab Funct Imaging, Tianjin 300052, Peoples R China

来源：

ACS NANO | 2023年 / 17卷 / 16期

基金：

中国国家自然科学基金;

关键词：

Immunometabolic reprogramming; Alzheimer'sdisease; brain energy metabolism; microglial polarization; nanomedicine; Akt; mTOR; HIF-1 & alpha; signaling; F-18-FDG PET; MEMORY; NANOPARTICLES;

D O I：

10.1021/acsnano.3c03232

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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-1a 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 F-18-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.

引用

页码：15724 / 15741

页数：18