Glypican 4 Regulates Aβ Internalization in Neural Stem Cells Partly via Low-Density Lipoprotein Receptor-Related Protein 1.
Glypican 4 Regulates Aβ Internalization in Neural Stem Cells Partly via Low-Density Lipoprotein Receptor-Related Protein 1.
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磷脂酰肌醇蛋白聚糖 4 部分通过低密度脂蛋白受体相关蛋白 1 调节神经干细胞中的 Aβ 内化
DOI：
10.3389/fncel.2021.732429
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发表时间：
2021
影响因子：
5.3
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Ma K;Xing S;Luan Y;Zhang C;Liu Y;Fei Y;Zhang Z;Liu Y;Chen X
神经干细胞（NSC）损伤已在阿尔茨海默病患者中报道。细胞内Aβ在神经干细胞损伤中起重要作用。硫酸乙酰肝素蛋白聚糖是脑中Aβ富集的有效介质。我们假设硫酸乙酰肝素蛋白聚糖磷脂酰肌醇蛋白聚糖4（Gpc 4）调节神经干细胞的Aβ内化。我们使用免疫荧光法评估了P0-P2代NSC中Gpc 4的表达。腺病毒和慢病毒分别用于调节NSC和APP/PS1小鼠中Gpc 4的表达。采用免疫共沉淀法确定Gpc 4、Aβ和低密度脂蛋白受体相关蛋白1（LRP 1）之间的关系。采用酶联免疫吸附试验和免疫荧光法检测细胞内Aβ浓度。使用JC-1试剂盒、末端脱氧核苷酸转移酶dUPT缺口末端标记和蛋白质印迹法评价Gpc 4/LRP 1在毒性/物理性Aβ诱导效应中的作用。Gpc 4在神经干细胞、神经元和星形胶质细胞中稳定表达。Gpc 4在神经干细胞中被Aβ上调并调节Aβ的内化。Gpc 4衰减减少Aβ摄取; Gpc 4过表达增加Aβ摄取。Gpc 4通过LRP 1调节Aβ内化，并部分通过LRP 1促进Aβ内化和Aβ诱导的线粒体膜电位和细胞凋亡的毒性/物理浓度。因此，Gpc 4是神经干细胞中Aβ富集的关键调节因子。抑制Gpc 4可挽救Aβ诱导的毒性作用，并将无毒Aβ富集减弱为细胞内毒性浓度。Gpc 4部分通过LRP 1参与Aβ内化和Aβ诱导的线粒体膜电位损伤和细胞凋亡的毒性/物理浓度。这些发现表明Gpc 4通过靶向NSC在早期治疗阿尔茨海默病中的潜在作用。
Neural stem cell (NSC) damage has been reported in patients with Alzheimer’s disease. Intracellular Aβ plays a vital role in NSC damage. Heparan sulfate proteoglycans are potent mediators of Aβ enrichment in the brain. We hypothesized the heparan sulfate proteoglycan glypican 4 (Gpc4) regulates Aβ internalization by NSCs. We evaluated Gpc4 expression in NSCs from P0–P2 generations using immunofluorescence. Adenovirus and lentivirus were used to regulate Gpc4 expression in NSCs and APP/PS1 mice, respectively. Co-immunoprecipitation was used to determine the relationship between Gpc4, Aβ, and low-density lipoprotein receptor-related protein 1 (LRP1). Intracellular Aβ concentrations were detected using enzyme-linked immunosorbent assay and immunofluorescence. The role of Gpc4/LRP1 on toxic/physical Aβ-induced effects was evaluated using the JC-1 kit, terminal deoxynucleotidyl transferase dUPT nick end labeling, and western blotting. Gpc4 was stably expressed in NSCs, neurons, and astrocytes. Gpc4 was upregulated by Aβ in NSCs and regulated Aβ internalization. Gpc4 attenuation reduced Aβ uptake; Gpc4 overexpression increased Aβ uptake. Gpc4 regulated Aβ internalization through LRP1 and contributed to Aβ internalization and toxic/physical concentrations of Aβ-induced mitochondrial membrane potential and cell apoptosis, partly via LRP1. Therefore, Gpc4 is a key regulator of Aβ enrichment in NSCs. Inhibiting Gpc4 rescued the Aβ-induced toxic effect and attenuated the nontoxic Aβ enrichment into intracellular toxic concentrations. Gpc4 contributed to Aβ internalization and toxic/physical concentrations of Aβ-induced mitochondrial membrane potential damage and cell apoptosis, partly via LRP1. These findings suggest a potential role of Gpc4 in treating Alzheimer’s disease at an early stage, by targeting NSCs.
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影响因子：
9.8
作者：
Blanchette CR;Perrat PN;Thackeray A;Bénard CY
通讯作者：
Bénard CY
影响因子：
5.6
作者：
Gao, Yunling;Liu, Qing;Xu, Fuqiang
通讯作者：
Xu, Fuqiang
纳米制剂介导的多功能干细胞疗法可改善阿尔茨海默病的β-淀粉样蛋白清除和神经再生
影响因子：
29.4
作者：
Huang, Dehua;Cao, Yuheng;Wang, Qiangbin
通讯作者：
Wang, Qiangbin
影响因子：
2.2
作者：
Du, Yayun;Liu, Xiaoli;Wu, Xiaopan
通讯作者：
Wu, Xiaopan
影响因子：
2.1
作者：
Gilat-Frenkel M;Boehm-Cagan A;Liraz O;Xian X;Herz J;Michaelson DM
通讯作者：
Michaelson DM