小胶质细胞核黄素代谢的仿生重塑通过调节神经炎症改善认知障碍,Advanced Science

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小胶质细胞核黄素代谢的仿生重塑通过调节神经炎症改善认知障碍
Advanced Science ( IF 14.3 ) Pub Date : 2023-02-17 , DOI: 10.1002/advs.202300180
Mengran Zhang ₁ , Huaqing Chen ₂ , Wenlong Zhang ₃ , Yan Liu ₄ , Liuyan Ding ₃ , Junwei Gong ₁ , Runfang Ma ₁ , Shaohui Zheng ₁ , Yunlong Zhang ₁

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神经炎症，其中小胶质细胞是主要贡献者，是认知功能障碍的重要危险因素。核黄素（也称为维生素 B2）通过抗氧化应激和抗炎特性改善认知障碍；然而，将核黄素代谢与认知障碍中的小胶质细胞功能联系起来的潜在机制仍不清楚。在这里，证明核黄素激酶 (RFK) 是核黄素代谢中的一种关键酶，它在小胶质细胞中特异性表达。核黄素的中间产物黄素单核苷酸 (FMN) 通过调节赖氨酸特异性甲基转移酶 2B (KMT2B) 抑制 RFK 表达。FMN 补充剂减弱了促炎性 TNFR1/NF- κB 信号通路，并且这种作用被 KMT2B 过表达所消除。为了提高游离 FMN 有限的抗炎效率，建立了一种仿生小胶质细胞纳米颗粒策略（指定为 MNPs@FMN），该策略穿透血脑屏障，增强小胶质细胞靶向递送效率。值得注意的是，MNPs@FMN 改善了脂多糖诱导的炎症小鼠模型和阿尔茨海默病 5xFAD 小鼠模型中的认知障碍和功能失调的突触可塑性。总之，FMN 的仿生小胶质细胞递送可作为炎症依赖性认知衰退的潜在治疗方法。

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Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation

Neuroinflammation, for which microglia are the predominant contributors, is a significant risk factor for cognitive dysfunction. Riboflavin (also known as vitamin B2) ameliorates cognitive impairment via anti-oxidative stress and anti-inflammation properties; however, the underlying mechanisms linking riboflavin metabolism and microglial function in cognitive impairment remain unclear. Here, it is demonstrated that riboflavin kinase (RFK), a critical enzyme in riboflavin metabolism, is specifically expressed in microglia. An intermediate product of riboflavin, flavin mononucleotide (FMN), inhibited RFK expression via regulation of lysine-specific methyltransferase 2B (KMT2B). FMN supplementation attenuated the pro-inflammatory TNFR1/NF-κB signaling pathway, and this effect is abolished by KMT2B overexpression. To improve the limited anti-inflammatory efficiency of free FMN, a biomimetic microglial nanoparticle strategy (designated as MNPs@FMN) is established, which penetrated the blood brain barrier with enhanced microglial-targeted delivery efficiency. Notably, MNPs@FMN ameliorated cognitive impairment and dysfunctional synaptic plasticity in a lipopolysaccharide-induced inflammatory mouse model and in a 5xFAD mouse model of Alzheimer's disease. Taken together, biomimetic microglial delivery of FMN may serve as a potential therapeutic approach for inflammation-dependent cognitive decline.

更新日期：2023-02-17

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