Attenuating vascular stenosis-induced astrogliosis preserves white matter integrity and cognitive function.
Attenuating vascular stenosis-induced astrogliosis preserves white matter integrity and cognitive function.
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DOI：
10.1186/s12974-021-02234-8
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发表时间：
2021-08-28
影响因子：
9.3
通讯作者：
Sun D
中科院分区：
文献类型：
--
作者：
Liu Q;Bhuiyan MIH;Liu R;Song S;Begum G;Young CB;Foley LM;Chen F;Hitchens TK;Cao G;Chattopadhyay A;He L;Sun D
慢性脑灌注不足（CCH）会导致白质损伤和认知障碍，其中星形胶质细胞增生是主要病理。然而，潜在的细胞机制尚未明确定义。反应性星形胶质细胞中 Na+/H+ 交换器 1 (NHE1) 的激活会导致星形胶质细胞肥大和肿胀。在这项研究中，我们在双侧颈动脉狭窄 (BCAS) 小鼠 CCH 模型中检查了 NHE1 蛋白在星形胶质细胞增生、白质脱髓鞘和认知功能中的作用。接受载体或选择性NHE1抑制剂HOE642的假手术小鼠、BCAS小鼠或BCAS小鼠被监测28天的区域脑血流和行为表现的变化。随后进行离体 MRI-DTI 检测脑损伤和脱髓鞘。通过免疫荧光染色进一步检查星形胶质细胞增生和脱髓鞘。通过批量 RNA 测序和 RT-qPCR 分析星形胶质细胞转录谱。在 BCAS 小鼠中检测到慢性脑血流量减少和空间工作记忆缺陷，并且 MRI DTI 分析中胼胝体、外囊和海马的平均分数各向异性 (FA) 值显着降低。与假手术对照小鼠相比，BCAS 小鼠表现出脱髓鞘和轴突损伤，并且 GFAP+ 星形胶质细胞和 Iba1+ 小胶质细胞增加。用其抑制剂 HOE642 对 NHE1 蛋白进行药理抑制，可以防止 BCAS 诱导的神经胶质增生、白质束和海马体的损伤，并显着改善认知能力。转录组和免疫染色分析进一步表明，NHE1 抑制特异性减弱促炎途径和 NADPH 氧化酶激活。我们的研究表明，NHE1 蛋白参与了 CCH 诱导的星形胶质细胞增生和促炎症转化，并且其阻断具有减少星形胶质细胞增生、脱髓鞘和认知障碍的潜力。在线版本包含可在 10.1186/s12974-021-02234-8 获取的补充材料。
Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na+/H+ exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS). Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR. Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP+ astrocytes and Iba1+ microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation. Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment. The online version contains supplementary material available at 10.1186/s12974-021-02234-8.
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影响因子：
6.2
作者：
Begum G;Song S;Wang S;Zhao H;Bhuiyan MIH;Li E;Nepomuceno R;Ye Q;Sun M;Calderon MJ;Stolz DB;St Croix C;Watkins SC;Chen Y;He P;Shull GE;Sun D
通讯作者：
Sun D
影响因子：
3.7
作者：
Cengiz P;Kintner DB;Chanana V;Yuan H;Akture E;Kendigelen P;Begum G;Fidan E;Uluc K;Ferrazzano P;Sun D
通讯作者：
Sun D
DOI：
10.1016/j.trci.2019.09.017
发表时间：
2019-01-01
影响因子：
4.8
作者：
Gladman, Jordan T.;Corriveau, Roderick A.;Biessels, Geert Jan
通讯作者：
Biessels, Geert Jan
影响因子：
9.3
作者：
Das, Sudeshna;Li, Zhaozhi;Serrano-Pozo, Alberto
通讯作者：
Serrano-Pozo, Alberto
影响因子：
3.7
作者：
Al-Onaizi, Mohammed A.;Parfitt, Gustavo M.;Prado, Vania F.
通讯作者：
Prado, Vania F.