Phospholipase D Family Member 4 Regulates Microglial Phagocytosis and Remyelination via the AKT Pathway in a Cuprizone-Induced Multiple Sclerosis Mouse Model

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-11-15 DOI:10.1111/cns.70111

Ran Sun, Tengyun Ma, Zheng Zhao, Yan Gao, Juan Feng, Xue Yang

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Abstract

Aims

Remyelination is an endogenous repair process that is often deficient in multiple sclerosis (MS). Stimulation of remyelination is thought to help limit the progression of MS. This study aimed to investigate the expression pattern and function of a microglial phagocytosis-related gene, phospholipase D family member 4 (PLD4), in a cuprizone (CPZ)-induced MS mouse model.

Methods

The extent of remyelination was assessed using LFB staining. Myelin phagocytosis assay was used to investigate the effect of Pld4 on microglial phagocytic activity.

Results

Pld4 was upregulated in the corpus callosum during demyelination and remyelination. AAV9-mediated Pld4 deficiency impaired remyelination and reduced the number of Olig2-positive cells. In the corpus callosum of Pld4-deficient mice, the microglial phagocytosis marker MAC2 was reduced, accompanied by inhibition of TrkA/AKT signaling. Similarly, the phagocytosis assay showed that Pld4 knockdown significantly inhibited myelin debris phagocytosis by BV2 cells. The AKT activator SC79 reversed the Pld4 deficiency-induced inhibition of microglial phagocytic activity and rescued the impaired remyelination in Pld4-deficient mice.

Conclusion

PLD4 is upregulated in CPZ-induced MS and modulates microglial phagocytosis and remyelination via the AKT pathway. Our findings provide experimental evidence for a better understanding of the molecular mechanism of MS.

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磷脂酶 D 家族成员 4 在铜绿素诱导的多发性硬化症小鼠模型中通过 AKT 通路调控小胶质细胞的吞噬作用和再髓鞘化作用

目的：再髓鞘化是一种内源性修复过程，多发性硬化症（MS）患者通常缺乏这一过程。刺激再髓鞘化被认为有助于限制多发性硬化症的进展。本研究旨在调查小胶质细胞吞噬相关基因磷脂酶D家族成员4（PLD4）在铜试剂（CPZ）诱导的多发性硬化症小鼠模型中的表达模式和功能：方法：用LFB染色法评估髓鞘再形成的程度。方法：用LFB染色法评估髓鞘再形成的程度，用髓鞘吞噬试验研究Pld4对小胶质细胞吞噬活性的影响：结果：在脱髓鞘和再髓鞘化过程中，Pld4在胼胝体中上调。AAV9介导的Pld4缺乏会影响髓鞘再形成，并减少Olig2阳性细胞的数量。在Pld4缺陷小鼠的胼胝体中，小胶质细胞吞噬标记物MAC2减少，同时TrkA/AKT信号也受到抑制。同样，吞噬试验显示，Pld4 基因敲除显著抑制了 BV2 细胞对髓鞘碎片的吞噬。AKT激活剂SC79逆转了Pld4缺陷诱导的小胶质细胞吞噬活性抑制，并挽救了Pld4缺陷小鼠受损的髓鞘再形成：结论：PLD4在CPZ诱导的多发性硬化症中上调，并通过AKT途径调节小胶质细胞的吞噬和髓鞘再形成。我们的发现为更好地理解多发性硬化症的分子机制提供了实验证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.