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Microenvironment Remodeling Micelles for Alzheimer's Disease Therapy by Early Modulation of Activated Microglia
Yifei Lu1, Zhongyuan Guo1, Yujie Zhang1
1Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Medical Neurobiology Research Center on Aging and Medicine Department of Pharmaceutics School of Pharmacy Fudan University Shanghai 201203 China.
Abstract:
Current strategies for Alzheimer's disease (AD) treatments focus on pathologies in the late stage of the disease progression. Poor clinical outcomes are displayed due to the irreversible damages caused by early microglia abnormality which triggers disease development before identical symptoms emerge. Based on the crosstalk between microglia and brain microenvironment, a reactive oxygen species (ROS)-responsive polymeric micelle system (Ab-PEG-LysB/curcumin (APLB/CUR)) is reported to normalize the oxidative and inflammatory microenvironment and reeducate microglia from an early phase of AD. Through an β-amyloid (Aβ) transportation-mimicked pathway, the micelles can accumulate into the diseased regions and exert synergistic effects of polymer-based ROS scavenging and cargo-based Aβ inhibition upon microenvironment stimuli. This multitarget strategy exhibits gradual correction of the brain microenvironment, efficient neuroprotection, and microglia modulation, leading to decreased Aβ plaque burdens and consequently enhanced cognitive functions in APPswe/PSEN1dE9 model mice. The results indicate that microglia can be exploited as an early target for AD treatment and their states can be controlled via microenvironment modulation.
Insights
This study introduces a novel micelle system to target early Alzheimer's disease (AD) by normalizing the brain microenvironment and modulating microglia. This approach reduces amyloid plaques and improves cognitive function in mice.
Area of Science:
- Biomedical Engineering
- Neuroscience
- Drug Delivery Systems
Background:
- Current Alzheimer's disease (AD) treatments target late-stage pathologies, leading to poor outcomes due to irreversible early damage from microglia abnormalities.
- Microglia dysfunction precedes overt symptoms, highlighting its role in initiating AD development.
- The brain microenvironment and microglia exhibit critical crosstalk influencing disease progression.
Purpose of the Study:
- To develop a reactive oxygen species (ROS)-responsive polymeric micelle system (Ab-PEG-LysB/curcumin (APLB/CUR)) for early-stage AD intervention.
- To normalize the oxidative and inflammatory brain microenvironment and reeducate aberrant microglia.
- To investigate the therapeutic potential of targeting microglia via microenvironment modulation.
Main Methods:
- Fabrication of a dual-functional micelle system (APLB/CUR) responsive to ROS and mimicking amyloid-beta (Aβ) transport.
- Administration of the micelle system to APPswe/PSEN1dE9 model mice.
- Evaluation of microenvironment normalization, microglia modulation, Aβ plaque burden, and cognitive function.
Main Results:
- The APLB/CUR micelles accumulated in diseased brain regions and exerted synergistic ROS scavenging and Aβ inhibition.
- The treatment gradually corrected the brain microenvironment, offering neuroprotection and modulating microglia.
- Significant reduction in Aβ plaque burden and enhancement of cognitive functions were observed in treated mice.
Conclusions:
- Microglia can be effectively targeted in the early stages of Alzheimer's disease.
- Modulating the brain microenvironment is a viable strategy to control microglia states for AD treatment.
- The developed micelle system shows promise for early AD intervention by addressing both microenvironment and pathological hallmarks.