Lu Yifei, Guo Zhongyuan, Zhang Yujie, Li Chao, Zhang Yu, Guo Qin, Chen Qinjun, Chen Xinli, He Xi, Liu Lisha, Ruan Chunhui, Sun Tao, Ji Bin, Lu Weigen, Jiang Chen
Key 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.
Department of Functional Brain Imaging Research National Institute of Radiological Sciences National Institute for Quantum and Radiological Science and Technology Chiba 263-8555 Japan.
Adv Sci (Weinh). 2018 Dec 12;6(4):1801586. doi: 10.1002/advs.201801586. eCollection 2019 Feb 20.
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.
目前治疗阿尔茨海默病（AD）的策略集中在疾病进展后期的病理变化上。由于早期小胶质细胞异常引发疾病发展，在相同症状出现之前就造成了不可逆的损害，导致临床疗效不佳。基于小胶质细胞与脑微环境之间的相互作用，据报道一种活性氧（ROS）响应性聚合物胶束系统（Ab-PEG-LysB/姜黄素（APLB/CUR））可使氧化和炎症微环境正常化，并在AD早期阶段对小胶质细胞进行重塑。通过模拟β-淀粉样蛋白（Aβ）转运的途径，胶束可积聚到病变区域，并在微环境刺激下发挥基于聚合物的ROS清除和基于载药的Aβ抑制的协同作用。这种多靶点策略表现出对脑微环境的逐步纠正、有效的神经保护和小胶质细胞调节，导致Aβ斑块负担减轻，从而增强APPswe/PSEN1dE9模型小鼠的认知功能。结果表明，小胶质细胞可作为AD治疗的早期靶点，其状态可通过微环境调节来控制。
