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Published on: August 15, 2019
Intranasal Delivery of Pure Nanodrug Loaded Liposomes for Alzheimer's Disease Treatment by Efficiently Regulating
Qianhua Feng1,2, Xueli Zhang1, Xiaowen Zhao1
1School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, P. R. China.
Abstract:
The activated M1-like microglia induced neuroinflammation is the critical pathogenic event in Alzheimer's disease (AD). Microglial polarization from pro-inflammatory M1 toward anti-inflammatory M2 phenotype is a promising strategy. To efficiently accomplish this, amyloid-β (Aβ) aggregates as the culprit of M1 microglia activation should be uprooted. Interestingly, this study finds out that the self-reassembly of curcumin molecules into carrier-free curcumin nanoparticles (CNPs) exhibits multivalent binding with Aβ to achieve higher inhibitory effect on Aβ aggregation, compared to free curcumin with monovalent effect. Based on this, the CNPs loaded cardiolipin liposomes are developed for efficient microglial polarization. After intranasal administration, the liposomes decompose to release CNPs and cardiolipin in response to AD oxidative microenvironment. The CNPs inhibit Aβ aggregation and promote Aβ phagocytosis/clearance in microglia, removing roadblock to microglial polarization. Subsequently, CNPs are endocytosed by microglia and inhibit TLR4/NF-κB pathway for microglia polarization (M1→M2). Meanwhile, cardiolipin is identified as signaling molecule to normalize microglial dysfunction to prevent pro-inflammatory factors release. In AD transgenic mice, neuroinflammation, Aβ burden, and memory deficits are relieved after treatment. Through combined attack by extracellularly eradicating roadblock of Aβ aggregation and intracellularly inhibiting inflammation-related pathways, this nanotechnology assisted delivery system polarizes microglia efficiently, providing a reliable strategy in AD treatment.
Insights
This study developed curcumin nanoparticles (CNPs) in liposomes to treat Alzheimer's disease (AD). The treatment effectively reduced neuroinflammation and improved memory deficits by reprogramming microglia towards an anti-inflammatory state.
Area of Science:
- Neuroscience
- Nanotechnology
- Pharmacology
Background:
- Neuroinflammation driven by M1-like microglia is central to Alzheimer's disease (AD) pathogenesis.
- Shifting microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype is a key therapeutic strategy.
- Amyloid-beta (Aβ) aggregates activate M1 microglia, necessitating their removal or inhibition.
Purpose of the Study:
- To develop a nanotechnology-based delivery system for efficient microglial polarization in AD.
- To investigate the therapeutic potential of curcumin nanoparticles (CNPs) and cardiolipin in modulating microglial phenotype and AD pathology.
Main Methods:
- Self-assembled, carrier-free curcumin nanoparticles (CNPs) were synthesized for enhanced Aβ binding and aggregation inhibition.
- CNPs were loaded into cardiolipin liposomes for intranasal delivery, designed to release cargo in the AD microenvironment.
- The effects of CNPs and cardiolipin on microglial polarization (M1→M2), Aβ clearance, and neuroinflammation were assessed in AD transgenic mice.
Main Results:
- CNPs demonstrated superior inhibition of Aβ aggregation compared to free curcumin due to multivalent binding.
- Intranasal administration led to liposome decomposition, releasing CNPs and cardiolipin, which inhibited Aβ aggregation and promoted microglial phagocytosis.
- Treatment effectively polarized microglia from M1 to M2, inhibited the TLR4/NF-κB pathway, normalized microglial dysfunction, and reduced neuroinflammation and memory deficits in AD mice.
Conclusions:
- The developed nanotechnology-assisted delivery system efficiently polarizes microglia, offering a promising strategy for AD treatment.
- Combined extracellular Aβ clearance and intracellular anti-inflammatory pathway modulation represent a reliable approach for AD therapy.
