Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer's pathology.
Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer's pathology.
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DOI：
10.1186/s40035-023-00393-7
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发表时间：
2024-01-04
影响因子：
12.6
通讯作者：
Moghe, Prabhas V.
中科院分区：
文献类型：
--
作者：
Gebril, Hoda M.;Aryasomayajula, Aravind;de Lima, Mariana Reis Nogueira;Uhrich, Kathryn E.;Moghe, Prabhas V.
关键词：
阿尔茨海默病（AD）被认为具有多因素病因。 AD的特点是进行性神经退行性变，其特点是老年人记忆力丧失加深和死亡率高。据信，AD 中的神经变性在细胞外淀粉样蛋白 (Aβ) 斑块、不受控制的小胶质细胞激活和神经炎症的相互关联级联作用下加剧。目前的 AD 疗法大多是针对症状而设计的，而解决该疾病的机制触发因素的能力有限。在这项研究中，我们报告了一种基于小胶质细胞清道夫受体（SR）靶向两亲纳米粒子（NP）的新型纳米技术，用于聚合减轻原纤维 Aβ（fAβ）负担、小胶质细胞调节和神经保护。我们设计了一种纳米技术方法来调节小胶质细胞内 SR 介导的细胞内 fAβ 运输。我们合成了 SR 靶向糖基两亲性大分子 (AM)，并使用它们作为生物活性壳，通过快速纳米沉淀制备血清稳定的 AM-NP。使用电子显微镜、体外方法、ELISA 和共聚焦显微镜，我们研究了 AM-NPs 对 BV2 小胶质细胞和 SH-SY5Y 神经母细胞瘤细胞系中 Aβ 纤维化、fAβ 介导的小胶质细胞炎症和神经毒性的影响。 AM-NPs 中断 Aβ 纤维化，通过靶向 fAβ 特异性 SR 减弱 fAβ 小胶质细胞内化，抑制 fAβ 介导的小胶质细胞激活和促炎症反应，并加速细胞内 fAβ 的溶酶体降解。此外，AM-NPs 可以抵消暴露于 fAβ 后小胶质细胞介导的神经毒性。 AM-NP 纳米技术提出了一种多因素策略，以靶向病理性 Aβ 聚集并阻止小胶质细胞和神经元中 fAβ 介导的病理进展。在线版本包含可在 10.1186/s40035-023-00393-7 获取的补充材料。
Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection. We designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM–NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM–NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines. AM–NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM–NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ. The AM–NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons. The online version contains supplementary material available at 10.1186/s40035-023-00393-7.
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