Multifunctional Liposomes Reduce Brain β-Amyloid Burden and Ameliorate Memory Impairment in Alzheimer's Disease Mouse Models
Multifunctional Liposomes Reduce Brain β-Amyloid Burden and Ameliorate Memory Impairment in Alzheimer's Disease Mouse Models
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DOI：
10.1523/jneurosci.0284-14.2014
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发表时间：
2014-10-15
影响因子：
5.3
通讯作者：
Re, Francesca
中科院分区：
文献类型：
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作者：
Balducci, Claudia;Mancini, Simona;Re, Francesca
阿尔茨海默病的特征在于β-淀粉样蛋白（A β）肽的斑块在脑中的积累和沉积。鉴于其关键作用，需要针对A β的新疗法。我们合理地设计了靶向大脑并促进A β组装体解聚的脂质体，并评估了它们在阿尔茨海默病小鼠模型中降低A β负荷的效率。脂质体用衍生自载脂蛋白-E受体结合结构域的肽双功能化用于血脑屏障靶向，并用磷脂酸双功能化用于A β结合。双功能化脂质体显示出在体外阻碍A β组装体形成和解聚的独特能力（EM实验）。通过ELISA评估，向APP/早老素1转基因小鼠（10个月大）给予双功能化脂质体3周（每周注射3次），减少了总脑不溶性A β 1-42（-33%），并减少了组织学检测到的斑块数量和总面积（-34%）。此外，如通过SDS-PAGE评估的，脑A β寡聚体减少（~ 70.5%）。在APP 23转基因小鼠（15月龄）中，通过组织学或用[C-11]匹兹堡化合物B（PI B）进行PET成像证实了斑块减少。脑A β的减少与肝脏（+18%）和脾脏（+20%）的增加有关。值得注意的是，新物体识别测试表明，治疗改善了小鼠受损的记忆。最后，脂质体以完整的形式到达大脑，如通过荧光标记的脂质体的共聚焦显微镜实验所确定的。这些数据表明，双功能化脂质体使脑A β聚集体不稳定，并促进肽穿过血脑屏障及其外周清除。这种一体化多任务治疗设备可以被认为是治疗阿尔茨海默病的候选者。
Alzheimer's disease is characterized by the accumulation and deposition of plaques of beta-amyloid (A beta) peptide in the brain. Given its pivotal role, new therapies targeting A beta are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of A beta assemblies and evaluated their efficiency in reducing the A beta burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood-brain barrier targeting and with phosphatidic acid for A beta binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, A beta assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble A beta 1-42 (-33%), assessed by ELISA, and the number and total area of plaques (-34%) detected histologically. Also, brain A beta oligomers were reduced (-70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [C-11] Pittsburgh compound B (PIB). The reduction of brain A beta was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain A beta aggregates and promote peptide removal across the blood-brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease.