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少突胶质细胞来源的包含 SIRT2 的外泌体通过 AKT/GSK-3β 通路改善抑郁小鼠的抑郁样行为，并恢复海马神经发生和突触可塑性。

Oligodendrocyte-derived exosomes-containing SIRT2 ameliorates depressive-like behaviors and restores hippocampal neurogenesis and synaptic plasticity via the AKT/GSK-3β pathway in depressed mice.

机构信息

Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

Clinical College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China.

出版信息

CNS Neurosci Ther. 2024 Mar;30(3):e14661. doi: 10.1111/cns.14661.

DOI:10.1111/cns.14661
PMID:38439616
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10912796/
Abstract

AIMS

To investigate the antidepressant role of oligodendrocyte-derived exosomes (ODEXs)-containing sirtuin 2 (SIRT2) and the underlying mechanism both in vivo and in vitro.

METHODS

Oligodendrocyte-derived exosomes isolated from mouse serum were administered to mice with chronic unpredictable mild stress (CUMS)-induced depression via the tail vein. The antidepressant effects of ODEXs were assessed through behavioral tests and quantification of alterations in hippocampal neuroplasticity. The role of SIRT2 was confirmed using the selective inhibitor AK-7. Neural stem/progenitor cells (NSPCs) were used to further validate the impact of overexpressed SIRT2 and ODEXs on neurogenesis and synapse formation in vitro.

RESULTS

Oligodendrocyte-derived exosome treatment alleviated depressive-like behaviors and restored neurogenesis and synaptic plasticity in CUMS mice. SIRT2 was enriched in ODEXs, and blocking SIRT2 with AK-7 reversed the antidepressant effects of ODEXs. SIRT2 overexpression was sufficient to enhance neurogenesis and synaptic protein expression. Mechanistically, ODEXs mediated transcellular delivery of SIRT2, targeting AKT deacetylation and AKT/GSK-3β signaling to regulate neuroplasticity.

CONCLUSION

This study establishes how ODEXs improve depressive-like behaviors and hippocampal neuroplasticity and might provide a promising therapeutic approach for depression.

摘要

目的

研究含沉默调节蛋白 2（SIRT2）的少突胶质细胞衍生外泌体（ODex）在体内和体外的抗抑郁作用及其潜在机制。

方法

通过尾静脉将从小鼠血清中分离得到的少突胶质细胞衍生外泌体给予慢性不可预测轻度应激（CUMS）诱导抑郁的小鼠。通过行为测试和海马神经可塑性变化的定量评估，评估 ODex 的抗抑郁作用。使用选择性抑制剂 AK-7 来确认 SIRT2 的作用。神经干细胞/祖细胞（NSPCs）被用于进一步验证过表达 SIRT2 和 ODex 对体外神经发生和突触形成的影响。

结果

少突胶质细胞衍生外泌体治疗可减轻 CUMS 小鼠的抑郁样行为，并恢复其神经发生和突触可塑性。SIRT2 富含于 ODex 中，用 AK-7 阻断 SIRT2 可逆转 ODex 的抗抑郁作用。过表达 SIRT2 足以增强神经发生和突触蛋白表达。在机制上，ODex 通过细胞间传递 SIRT2，靶向 AKT 去乙酰化和 AKT/GSK-3β 信号通路来调节神经可塑性。

结论

本研究确立了 ODex 如何改善抑郁样行为和海马神经可塑性，并可能为抑郁症提供一种有前途的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/cd73342751ab/CNS-30-e14661-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/3f1e1b60953b/CNS-30-e14661-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/f49a73c82bbb/CNS-30-e14661-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/3697c128a839/CNS-30-e14661-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/e94b4556688f/CNS-30-e14661-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/80688dc73c1d/CNS-30-e14661-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/cd73342751ab/CNS-30-e14661-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/3f1e1b60953b/CNS-30-e14661-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/f49a73c82bbb/CNS-30-e14661-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/3697c128a839/CNS-30-e14661-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/e94b4556688f/CNS-30-e14661-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/80688dc73c1d/CNS-30-e14661-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a26/10912796/cd73342751ab/CNS-30-e14661-g006.jpg

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