Mitochondria-targeting Cu2-xSe-TPP with dual enzyme activity alleviates Alzheimer's disease by modulating oxidative
Liqiang Wang1, Xiaoyu Yuan2, Qianyu Cai2
1Shenzhen Longhua Maternity and Child Healthcare Hospital, Shenzhen 518110, China; College of Chemistry and Materials Science of Jinan University, Guangzhou 510632, China.
Abstract:
Mitochondrial dysfunction in microglia has been implicated as a key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). Abnormal production of reactive oxygen species (ROS) and neuroinflammation caused by mitochondrial oxidative stress are important factors leading to neuronal death in AD. Herein, a "dual brake" strategy to synergistically halt mitochondrial dysfunction and neuroinflammation targeting mitochondria in microglia is proposed. To achieve this goal, (3-carboxypropyl) triphenyl-phosphonium bromide (TPP)-modified Cu2-xSe nanozymes (Cu2-xSe-TPP NPs) with dual enzyme-like activities was designed. Cu2-xSe-TPP NPs with superoxide dismutase-mimetic (SOD) and catalase-mimetic (CAT) activities can effectively scavenge ROS in the mitochondria of microglia and relieve mitochondrial oxidative stress. In vivo studies demonstrated that Cu2-xSe-TPP NPs can alleviate oxidative stress and promote neuroprotection in the hippocampus of AD model mice. In addition, Cu2-xSe-TPP NPs can regulate the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, promote Aβ phagocytosis and reshape the AD inflammatory microenvironment, thus effectively attenuating AD neuropathology and rescuing cognitive deficits in AD model mice. Taken together, this strategy preventing mitochondrial damage and remodeling the inflammatory microenvironment will provide a new perspective for AD therapy.
Insights
This study introduces novel nanozymes that target mitochondrial dysfunction and neuroinflammation in Alzheimer's disease (AD). These nanozymes effectively reduce oxidative stress and inflammation, offering a promising new therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Biomaterials Science
- Nanotechnology
Background:
- Mitochondrial dysfunction in microglia is a key factor in Alzheimer's disease (AD) pathogenesis.
- Oxidative stress and neuroinflammation driven by mitochondrial dysfunction contribute to neuronal death in AD.
Purpose of the Study:
- To develop a "dual brake" strategy to simultaneously address mitochondrial dysfunction and neuroinflammation in microglia for AD therapy.
- To design and evaluate novel nanozymes for targeting mitochondria in microglia.
Main Methods:
- Synthesis of (3-carboxypropyl) triphenyl-phosphonium bromide (TPP)-modified Cu2-xSe nanozymes (Cu2-xSe-TPP NPs) with dual enzyme-like activities (superoxide dismutase-mimetic and catalase-mimetic).
- In vivo studies using AD model mice to assess the effects of Cu2-xSe-TPP NPs on oxidative stress, neuroinflammation, and cognitive deficits.
Main Results:
- Cu2-xSe-TPP NPs effectively scavenged reactive oxygen species (ROS) and alleviated mitochondrial oxidative stress in microglia.
- Nanozymes promoted neuroprotection in the hippocampus of AD model mice.
- Cu2-xSe-TPP NPs shifted microglial polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, enhanced Aβ phagocytosis, and improved cognitive function.
Conclusions:
- The developed Cu2-xSe-TPP NPs offer a synergistic approach to halt mitochondrial dysfunction and neuroinflammation in AD.
- This strategy of preventing mitochondrial damage and remodeling the inflammatory microenvironment presents a novel therapeutic perspective for Alzheimer's disease.
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