Extracellular vesicles derived from astrocyte-treated with haFGF(14-154) attenuate Alzheimer phenotype in AD mice.
Extracellular vesicles derived from astrocyte-treated with haFGF(14-154) attenuate Alzheimer phenotype in AD mice.
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DOI：
10.7150/thno.70951
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Huang, Yadong
中科院分区：
文献类型：
--
作者：
Peng, Dong;Wang, Youjin;Xiao, Yuanjie;Peng, Mengyuan;Mai, Wanwen;Hu, Bo;Jia, Yanbin;Chen, Hongxia;Yang, Yan;Xiang, Qi;Su, Zhijian;Zhang, Qihao;Huang, Yadong
背景资料：阿尔茨海默病（AD）患者血清和脑脊液中aFGF含量增加，并减弱星形胶质细胞的活化。细胞外囊泡（EV）是星形胶质细胞-神经元通讯的主要介质。由于过度或持续的反应性星形胶质细胞导致慢性炎症和神经功能障碍，并且星形胶质细胞的活化可以被aFGF抑制，我们提出星形胶质细胞衍生的EV（AEV）的货物可能被aFGF刺激修饰，在AD进展中起重要作用。然而，aFGF的作用机制仍不清楚。研究方法：从受损的星形胶质细胞中分离AEV，在Aβ负载条件下用或不用aFGF处理，并鼻内给予AD小鼠。我们确定了AEV进入大脑、改善认知行为缺陷、减轻大脑中的Aβ负荷和改善突触超微结构的能力。随后，对AEV中富集的miRNA进行测序，以鉴定aFGF特异性修饰的关键分子。最后，我们探讨了miR-206- 3 p抑制对认知缺陷的保护作用及其调控机制，并确定其作为潜在AD诊断的特异性生物标志物的作用。结果如下：aFGF刺激的AEV（定义为AEVs-Aβ+H）通过促进轴突生长和减少Aβ对神经元的负荷，在AD病理学中具有有利的神经保护作用。鼻内给药后，AEVs-Aβ+H改善了APP/PS1和Aβ脑注射小鼠的认知行为缺陷，促进了突触可塑性，并减轻了脑Aβ负荷。AEVs-Aβ+H对AD的有益作用与正常情况下产生的AEVs（AEVs-Ctrl）相似。aFGF刺激改变了Aβ损伤的星形胶质细胞衍生的EV中的货物，其中最显著的是miR-206- 3 p的下调。miR-206- 3 p水平在AD小鼠和患者的血浆中特别高，并且miR-206- 3 p阿托洛尔逆转了AD小鼠中的阿尔茨海默病表型。AD小鼠脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）基因受miR-206- 3 p负调控，AEVs-Aβ+H和miR-206- 3 p AEVs-Aβ + H上调。AEVs-Aβ+H通过miR-206- 3 p/BDNF轴抑制δ-分泌酶（天冬酰胺内肽酶，AEP）激活，以减轻AD脑中的Aβ负荷。结论：我们的研究结果强调了aFGF在AEV货物修饰中的作用，特别是miR-206- 3 p，其可潜在地用作AD诊断和治疗靶点的生物标志物。
Background: aFGF content in serum and cerebrospinal fluid is increased in Alzheimer's disease (AD) patients and attenuates the activation of astrocytes. Extracellular vesicles (EVs) are a major mediator in astrocyte-neuron communications. Since excessive or persistent reactive astrocytes lead to chronic inflammation and neuronal dysfunction, and the activation of astrocytes can be inhibited by aFGF, we proposed that the cargoes of astrocyte-derived EVs (AEVs) might be modified by aFGF stimulation, playing an important role in AD progression. However, the mechanisms underlying the role of aFGF remain unclear. Methods: AEVs were isolated from damaged astrocytes, treated with or without aFGF in Aβ-loading condition, and were intranasally administered to AD mice. We determined the ability of AEVs to enter the brain, ameliorate cognitive behavior deficits, alleviate the Aβ burden in the brain, and improve synapse ultrastructure. Subsequently, the miRNAs enriched in AEVs were sequenced to identify the key molecules specifically modified by aFGF. Finally, we explored the protective effects of miR-206-3p inhibition on cognitive deficiency and its regulatory mechanism and determined its role as a specific biomarker for potential AD diagnosis. Results: AEVs stimulated by aFGF (defined as AEVs-Aβ+H) had favorable neuroprotection in AD pathology by enhancing neurite growth and reduction of Aβ loading on neurons in vitro. Following intranasal administration, AEVs-Aβ+H ameliorated cognitive behavior deficits, promoted synaptic plasticity, and alleviated brain Aβ burden in the APP/PS1 and Aβ brain-injected mice. AEVs-Aβ+H showed beneficial effects on AD similar to AEVs produced in normal situations (AEVs-Ctrl). aFGF stimulation modified the cargoes in EVs derived from Aβ damaged astrocytes, the most significant of which being the down-regulation of miR-206-3p. The miR-206-3p level was specifically high in the plasma of AD mice and patients, and miR-206-3p antagomir reversed the Alzheimer phenotype in AD mice. The brain-derived neurotrophic factor (BDNF) gene was negatively regulated by miR-206-3p and upregulated by AEVs-Aβ+H and miR-206-3p antagomir in AD mice. AEVs-Aβ+H inhibited δ-secretase (Asparagine endopeptidase, AEP) activation via the miR-206-3p/BDNF axis to alleviate Aβ burden in the AD brain. Conclusion: Our findings highlight the role of aFGF in the modification of AEVs cargoes, especially miR-206-3p that can potentially serve as a biomarker for AD diagnosis and therapeutic target.
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影响因子：
4.3
作者：
Harada K;Kamiya T;Tsuboi T
通讯作者：
Tsuboi T
星形胶质细胞诱导的突触发生的分子机制。
影响因子：
5.7
作者：
Baldwin KT;Eroglu C
通讯作者：
Eroglu C
影响因子：
6.1
作者：
Chompre G;Cruz E;Maldonado L;Rivera-Amill V;Porter JT;Noel RJ Jr
通讯作者：
Noel RJ Jr
影响因子：
7.2
作者：
Bouleau, Sylvina;Parvu-Ferecatu, Ioana;Renaud, Flore
通讯作者：
Renaud, Flore
DOI：
10.1073/pnas.1320401111
发表时间：
2014-07-22
影响因子：
11.1
作者：
Kang, Wenfei;Balordi, Francesca;Hebert, Jean M.
通讯作者：
Hebert, Jean M.