少突胶质前体细胞吞噬作用诱导产生的聚集素在阿尔茨海默病模型中可阻断白细胞介素-9的分泌，从而抑制髓鞘形成。

Clusterin induced by OPC phagocytosis blocks IL-9 secretion to inhibit myelination in a model of Alzheimer's disease.

作者信息

Beiter Rebecca M, Raghavan Tula P, Suchocki Olivia, Ennerfelt Hannah E, Rivet-Noor Courtney R, Merchak Andrea R, Phillips Jennifer L, Bathe Tim, Lukens John R, Prokop Stefan, Dupree Jeffrey L, Gaultier Alban

机构信息

Center for Brain Immunology and Glia, Department of Neuroscience, Charlottesville, VA 22908, USA.

Graduate Program in Neuroscience, Charlottesville, VA 22908, USA.

出版信息

Heliyon. 2025 Jan 3;11(1):e41635. doi: 10.1016/j.heliyon.2025.e41635. eCollection 2025 Jan 15.

DOI:10.1016/j.heliyon.2025.e41635

PMID:39866464

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11761289/

Abstract

BACKGROUND

Variants in the gene have been identified as a risk factor for late-onset Alzheimer's disease and are linked to decreased white matter integrity in healthy adults. However, the specific role for clusterin in myelin maintenance in the context of Alzheimer's disease remains unclear.

METHODS

We employed a combination of immunofluorescence and transmission electron microscopy techniques, primary culture of OPCs, and an animal model of Alzheimer's disease.

RESULTS

We found that phagocytosis of debris such as amyloid beta, myelin, and apoptotic cells, increases clusterin expression in oligodendrocyte progenitors. We further discovered that exposure to clusterin inhibits differentiation of oligodendrocyte progenitors. Mechanistically, clusterin blunts production of IL-9 and addition of exogenous IL-9 can rescue clusterin-inhibited myelination. Lastly, we demonstrate that clusterin deletion in mice prevents myelin loss in the 5XFAD model.

DISCUSSION

Our data suggest that clusterin could play a key role in Alzheimer's disease myelin pathology.

摘要

背景

该基因的变异已被确定为晚发性阿尔茨海默病的一个风险因素，并且与健康成年人白质完整性下降有关。然而，在阿尔茨海默病背景下，簇集蛋白在髓鞘维持中的具体作用仍不清楚。

方法

我们采用了免疫荧光和透射电子显微镜技术、少突胶质前体细胞的原代培养以及阿尔茨海默病动物模型相结合的方法。

结果

我们发现，对诸如β淀粉样蛋白、髓鞘和凋亡细胞等碎片的吞噬作用会增加少突胶质前体细胞中簇集蛋白的表达。我们进一步发现，暴露于簇集蛋白会抑制少突胶质前体细胞的分化。从机制上讲，簇集蛋白会抑制白细胞介素-9的产生，而添加外源性白细胞介素-9可以挽救簇集蛋白抑制的髓鞘形成。最后，我们证明小鼠体内簇集蛋白的缺失可防止5XFAD模型中的髓鞘损失。