Impaired macroautophagy in oligodendrocyte precursor cells suppresses neuronal plasticity via a senescence-associated signaling

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-09-24 DOI:10.1126/sciadv.adq7665

Hong Chen, Yan-Yun Sun, Qi-Fa Li, Yu-Tong Du, Na-Na Hu, Ao-Ran Sui, Xiao-Qing Luo, Xin Huang, Chao Zhu, Gang Yang, Lin-Lin Yao, Yong Tang, Hua Hu, Chun-Feng Liu, Jin Tao, Lei Feng, Frank Kirchhoff, Wenhui Huang, Shao Li, Quan-Hong Ma

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Abstract

Aging drives cognitive decline in the adult brain with unclear mechanisms. Previously, oligodendrocyte precursor cells (OPCs), the source cells of myelin-forming cells in the central nervous system, have been linked to brain aging by their compromised differentiation and regeneration capability. Whether a myelination-independent function of OPCs is involved in brain aging remains unknown. In this study, we herein report a myelination-independent role of OPCs in exaggerating cognitive decline in the aging brain via suppressing neuronal plasticity. Our results demonstrate that macroautophagic flux declines in aged OPCs. Inactivation of autophagy promotes the senescence of OPCs, which activates C-C motif chemokine ligand 3 (CCL3)/CCL5–C-C motif chemokine receptor 5 signaling. Through this, autophagy-defective OPCs impair glutamatergic transmission, neuronal excitability, and long-term potentiation, exaggerating the cognitive decline in the aging brain. Our study demonstrates a myelination-independent role of OPCs in brain aging and identifies that a declined autophagy in OPCs is a pivotal factor in driving aging-associated cognitive decline.

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少突胶质前体细胞巨噬受损通过衰老相关信号抑制神经元可塑性

衰老导致成人大脑认知能力下降的机制尚不清楚。以前，少突胶质前体细胞（OPCs）是中枢神经系统髓磷脂形成细胞的来源细胞，通过其受损的分化和再生能力与大脑衰老有关。OPCs与髓鞘无关的功能是否参与脑老化仍不清楚。在这项研究中，我们在此报道了OPCs通过抑制神经元可塑性来夸大衰老大脑认知能力下降的髓鞘独立作用。我们的研究结果表明，大自噬通量在老年OPCs中下降。自噬失活促进OPCs衰老，激活C-C基序趋化因子配体3 (CCL3)/ CCL5-C-C基序趋化因子受体5信号通路。由此，自噬缺陷的OPCs损害了谷氨酸能传递、神经元兴奋性和长期增强，加剧了老化大脑的认知能力下降。我们的研究证明了OPCs在脑衰老中的髓鞘独立作用，并确定了OPCs自噬下降是驱动衰老相关认知能力下降的关键因素。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.