CD36‐Binding Amphiphilic Nanoparticles for Attenuation of α‐Synuclein‐Induced Microglial Activation
CD36‐Binding Amphiphilic Nanoparticles for Attenuation of α‐Synuclein‐Induced Microglial Activation
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CD36 — 结合两亲性纳米颗粒，用于减弱 α — 突触核蛋白 — 诱导的小胶质细胞激活
DOI：
10.1002/anbr.202100120
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发表时间：
2022
影响因子：
3.4
通讯作者：
Moghe, Prabhas V.
中科院分区：
文献类型：
--
作者：
Zhao, Nanxia;Francis, Nicola L.;Song, Shuang;Kholodovych, Vladyslav;Calvelli, Hannah R.;Hoop, Cody L.;Pang, Zhiping P.;Baum, Jean;Uhrich, Kathryn E.;Moghe, Prabhas V.
神经炎症是帕金森病（PD）病理学的标志之一，其中小胶质细胞活化是最早的事件之一，由细胞外α-突触核蛋白（aSYN）与分化簇36（CD 36）受体结合触发。本文中，含有基于酒石酸的两亲性大分子（AM）的CD 36结合纳米颗粒（NP）被合理地设计以抑制这种aSYN-CD 36结合。计算机对接显示，具有不同烷基侧链长度的四种AM呈现不同水平的CD 36结合亲和力，并且最佳烷基链长度促进对aSYN-CD 36相互作用的最强抑制活性。体外竞争性结合测定表明，基于AM的NP的抑制活性在12和18个碳的中间侧链长度处达到平台，支持计算机对接预测。这些中等长度的AM NP在减少aSYN内化和抑制来自aSYN攻击的小胶质细胞的促炎分子肿瘤坏死因子α（TNF-α）和一氧化氮方面也具有显著更强的作用。所有四种NP均调节aSYN攻击的小胶质细胞的基因表达，下调促炎基因TNF、白细胞介素6（IL-6）和IL-1β，上调抗炎基因转化生长因子β（TGF-β）和Arg 1表达。在本文中，总的来说，代表了一种新的聚合物纳米技术平台，其可用于调节aSYN诱导的小胶质细胞活化。
Neuroinflammation is one of the hallmarks contributing to Parkinson's disease (PD) pathology, where microglial activation occurs as one of the earliest events, triggered by extracellular α‐synuclein (aSYN) binding to the cluster of differentation 36 (CD36) receptor. Herein, CD36‐binding nanoparticles (NPs) containing tartaric acid–based amphiphilic macromolecules (AMs) are rationally designed to inhibit this aSYN–CD36 binding. In silico docking reveals that four AMs with varying alkyl side chain lengths present differential levels of CD36 binding affinity and that an optimal alkyl chain length promotes the strongest inhibitory activity toward aSYN–CD36 interactions. In vitro competitive binding assays indicate that the inhibitory activity of AM‐based NPs plateaus at intermediate side chain lengths of 12 and 18 carbons, supporting the in silico docking predictions. These intermediate‐length AM NPs also has significantly stronger effects on reducing aSYN internalization and inhibiting proinflammatory molecules tumor necrosis factor α (TNF‐α) and nitric oxide from aSYN‐challenged microglia. All four NPs modulate the gene expression of aSYN‐challenged microglia, downregulating proinflammatory genes TNF, interleukin 6 (IL‐6), and IL‐1β, and upregulating anti‐inflammatory genes transforming growth factor β (TGF‐β) and Arg1 expression. Herein, overall, a novel polymeric nanotechnology platform is represented that can be used to modulate aSYN‐induced microglial activation.