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NG2 胶质细胞通过抑制小胶质细胞向神经元的前列腺素 E2 信号传递来保护神经免受朊病毒毒性的侵害。

NG2 glia protect against prion neurotoxicity by inhibiting microglia-to-neuron prostaglandin E2 signaling.

机构信息

Institute of Neuropathology, University of Zurich, Zurich, Switzerland.

Karolinska Institutet, Department of Medicine Solna, Division of Rheumatology, Stockholm, Sweden.

出版信息

Nat Neurosci. 2024 Aug;27(8):1534-1544. doi: 10.1038/s41593-024-01663-x. Epub 2024 May 27.

DOI:10.1038/s41593-024-01663-x
PMID:38802591
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11303249/
Abstract

Oligodendrocyte-lineage cells, including NG2 glia, undergo prominent changes in various neurodegenerative disorders. Here, we identify a neuroprotective role for NG2 glia against prion toxicity. NG2 glia were activated after prion infection in cerebellar organotypic cultured slices (COCS) and in brains of prion-inoculated mice. In both model systems, depletion of NG2 glia exacerbated prion-induced neurodegeneration and accelerated prion pathology. Loss of NG2 glia enhanced the biosynthesis of prostaglandin E2 (PGE2) by microglia, which augmented prion neurotoxicity through binding to the EP4 receptor. Pharmacological or genetic inhibition of PGE2 biosynthesis attenuated prion-induced neurodegeneration in COCS and mice, reduced the enhanced neurodegeneration in NG2-glia-depleted COCS after prion infection, and dampened the acceleration of prion disease in NG2-glia-depleted mice. These data unveil a non-cell-autonomous interaction between NG2 glia and microglia in prion disease and suggest that PGE2 signaling may represent an actionable target against prion diseases.

摘要

少突胶质细胞谱系细胞，包括 NG2 神经胶质细胞，在各种神经退行性疾病中发生显著变化。在这里，我们发现 NG2 神经胶质细胞对朊病毒毒性具有神经保护作用。在小脑器官型培养切片（COCS）和朊病毒感染的小鼠脑中，NG2 神经胶质细胞在朊病毒感染后被激活。在这两种模型系统中，NG2 神经胶质细胞的耗竭加剧了朊病毒诱导的神经退行性变并加速了朊病毒病理学。NG2 神经胶质细胞的丧失增强了小胶质细胞中环加氧酶 2（COX2）衍生的前列腺素 E2（PGE2）的生物合成，通过与 EP4 受体结合增强了朊病毒的神经毒性。COCS 中 PGE2 生物合成的药理学或遗传抑制减轻了 COCS 中朊病毒诱导的神经退行性变和 NG2 神经胶质细胞耗竭后朊病毒感染引起的增强性神经退行性变，并抑制了 NG2 神经胶质细胞耗竭小鼠中朊病毒病的加速。这些数据揭示了朊病毒病中 NG2 神经胶质细胞和小胶质细胞之间的非细胞自主相互作用，并表明 PGE2 信号可能是针对朊病毒病的可行靶点。

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