mTOR-Mediated Immunometabolic Reprogramming Nanomodulators Enable Sensitive Switching of Energy Deprivation-Induced Microglial Polarization for Alzheimer's Disease Management.
Fan YangDongju ZhaoMeng ChengYining LiuZiyao ChenJin ChangYan DouPublished in: ACS nano (2023)
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 18 F-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.
Keyphrases
- cognitive decline
- inflammatory response
- neuropathic pain
- lipopolysaccharide induced
- positron emission tomography
- cell proliferation
- lps induced
- cancer therapy
- pet ct
- mild cognitive impairment
- signaling pathway
- white matter
- resting state
- pet imaging
- multiple sclerosis
- computed tomography
- cerebral ischemia
- drug delivery
- high glucose
- diabetic rats
- traumatic brain injury
- drug induced
- type diabetes
- oxidative stress
- functional connectivity
- metabolic syndrome
- adipose tissue
- climate change
- skeletal muscle
- spinal cord
- brain injury
- stress induced
- high resolution
- blood pressure