Exosomal miR-132-3p from mesenchymal stromal cells improves synaptic dysfunction and cognitive decline in vascular dementia.
Exosomal miR-132-3p from mesenchymal stromal cells improves synaptic dysfunction and cognitive decline in vascular dementia.
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来自间充质基质细胞的外泌体 miR-132-3p 可改善血管性痴呆的突触功能障碍和认知能力下降
DOI：
10.1186/s13287-022-02995-w
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发表时间：
2022-07-15
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
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作者：
血管性痴呆(VD)会导致认知和记忆障碍。外切体及其携带的microRNAs(MiRs)参与了间充质基质细胞的神经保护作用，miR-132-3p在神经元可塑性中起着关键作用。在此，我们研究了MSC EX及其miR-132-3p载体在拯救VD小鼠认知和记忆障碍中的作用及其机制。采用双侧颈总动脉结扎法制备小鼠VD模型。检测大鼠海马区和大脑皮层MIR-132-3p和MSC ex水平。在VD诱导后24小时，静脉注射感染对照慢病毒(Exon)、前miR-132-3p表达慢病毒(EXmiR-132-3p)或miR-132-3p抗慢病毒(EXantagomiR-132-3p)的MSC ex。进行行为和认知测试，并在VD后21天内处死小鼠。观察MSCex对大鼠海马和皮质神经元数量、突触可塑性、树突棘密度、Aβ和p Tau水平的影响。观察MSC ex对缺氧缺糖(OGD)损伤神经元的细胞凋亡、突起伸长和分支的影响。检测RAS、Akt、GSK-3β和Tau蛋白的表达水平。与正常小鼠相比，VD小鼠大脑皮质和海马区miR-132-3p和MSC ex水平显著降低。与激动子治疗相比，注射ExmiR-132-3p能更有效地改善VD小鼠的认知功能，增加大脑皮质和海马区miR-132-3p水平、神经元数目、突触可塑性和树突棘密度，降低Aβ和p-tau水平。相反，EXantagomiR-132-3p处理显著降低了大脑皮层和海马区miR-132-3p的表达，并减弱了EXmiR-132-3p处理引起的功能改善。在体外，ExmiR-132-3p可抑制RASA1蛋白的表达，增加RAS及Akt和GSK-3β的磷酸化，并通过传递miR-132-3p降低原代神经元中p-Tau的水平，从而减少缺氧损伤神经元的凋亡，增加突起的伸长和分支。我们的研究表明，miR-132-3p簇丰富的MSCex通过激活RASA1下调诱导的RAS/Akt/GSK-3β通路来改善神经元和突触功能，从而促进认知功能的恢复。网上版载有补充材料，可在10.1186/s13287-022-02995-w查阅。
Vascular dementia (VD) results in cognition and memory deficit. Exosomes and their carried microRNAs (miRs) contribute to the neuroprotective effects of mesenchymal stromal cells, and miR-132-3p plays a key role in neuron plasticity. Here, we investigated the role and underlying mechanism of MSC EX and their miR-132-3p cargo in rescuing cognition and memory deficit in VD mice. Bilateral carotid artery occlusion was used to generate a VD mouse model. MiR-132-3p and MSC EX levels in the hippocampus and cortex were measured. At 24-h post-VD induction, mice were administered with MSC EX infected with control lentivirus (EXCon), pre-miR-132-3p-expressing lentivirus (EXmiR-132-3p), or miR-132-3p antago lentivirus (EXantagomiR-132-3p) intravenously. Behavioral and cognitive tests were performed, and the mice were killed in 21 days after VD. The effects of MSC EX on neuron number, synaptic plasticity, dendritic spine density, and Aβ and p-Tau levels in the hippocampus and cortex were determined. The effects of MSC EX on oxygen–glucose deprivation (OGD)-injured neurons with respect to apoptosis, and neurite elongation and branching were determined. Finally, the expression levels of Ras, phosphorylation of Akt, GSK-3β, and Tau were also measured. Compared with normal mice, VD mice exhibited significantly decreased miR-132-3p and MSC EX levels in the cortex and hippocampus. Compared with EXCon treatment, the infusion of EXmiR-132-3p was more effective at improving cognitive function and increasing miR-132-3p level, neuron number, synaptic plasticity, and dendritic spine density, while decreasing Aβ and p-Tau levels in the cortex and hippocampus of VD mice. Conversely, EXantagomiR-132-3p treatment significantly decreased miR-132-3p expression in cortex and hippocampus, as well as attenuated EXmiR-132-3p treatment-induced functional improvement. In vitro, EXmiR-132-3p treatment inhibited RASA1 protein expression, but increased Ras and the phosphorylation of Akt and GSK-3β, and decreased p-Tau levels in primary neurons by delivering miR-132-3p, which resulted in reduced apoptosis, and increased neurite elongation and branching in OGD-injured neurons. Our studies suggest that miR-132-3p cluster-enriched MSC EX promotes the recovery of cognitive function by improving neuronal and synaptic dysfunction through activation of the Ras/Akt/GSK-3β pathway induced by downregulation of RASA1. The online version contains supplementary material available at 10.1186/s13287-022-02995-w.
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影响因子：
4.8
作者：
Galderisi U;Peluso G;Di Bernardo G
通讯作者：
Di Bernardo G
影响因子：
7.7
作者：
Alessio, Nicola;Squillaro, Tiziana;Galderis, Umberto
通讯作者：
Galderis, Umberto
DOI：
10.1126/science.1209236
发表时间：
2011-11-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ho VM;Lee JA;Martin KC
通讯作者：
Martin KC
影响因子：
4.8
作者：
de Godoy, Mariana A.;Saraiva, Leonardo M.;Ferreira, Sergio T.
通讯作者：
Ferreira, Sergio T.
DOI：
10.1002/stem.2626
发表时间：
2017-09-01
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
作者：
通讯作者：
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