小胶质细胞
磷酸化
老年斑
内吞作用
医学
药理学
β淀粉样蛋白
化学
肽
神经科学
癌症研究
阿尔茨海默病
内科学
生物
生物化学
炎症
受体
疾病
作者
Guochen Han,Kaiwen Bai,Xiaoyu Yang,Chenhua Sun,Ji Yi,Jianping Zhou,Huaqing Zhang,Yang Ding
标识
DOI:10.1002/advs.202106072
摘要
Amyloid-β (Aβ) toxicity is considered to be companioned by Tau phosphorylation in Alzheimer's disease (AD). The clinical AD therapy is usually subjected to low blood-brain barrier (BBB) penetration and complex interaction mechanisms between Aβ and phosphorylated Tau. A "Drug-Carrier" synergy therapy is herein designed to simultaneously target Aβ and Tau-associated pathways for AD treatment. To imitate natural nanoparticle configuration, the endogenous apolipoprotein A-I and its mimicking peptide 4F fused angiopep-2 (Ang) are sequentially grafted onto lipid nanocomposite (APLN), providing liberty of BBB crossing and microglia targeted Aβ clearance. For synergy treatment, methylene blue (MB) is further assembled into APLN (APLN/MB) for Tau aggregation inhibition. After intravenous administration, the optimized density (5 wt%) of Ang ligands dramatically enhances APLN/MB intracerebral shuttling and accumulation, which is 2.15-fold higher than that Ang absent-modification. The site-specific release of MB collaborates APLN to promote Aβ capture for microglia endocytosis clearance and reduce p-Tau level by 25.31% in AD pathogenesis. In AD-Aβ-Tau bearing mouse models, APLN/MB can relieve AD symptoms, rescue neuron viability and cognitive functions. Collectively, it is confirmed that "Drug-Carrier" synergy therapy of APLN/MB is a promising approach in the development of AD treatments.
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