Characterization of a Human Neuronal Culture System for the Study of Cofilin-Actin Rod Pathology.
Characterization of a Human Neuronal Culture System for the Study of Cofilin-Actin Rod Pathology.
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DOI：
10.3390/biomedicines11112942
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发表时间：
2023-10-31
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
辅乳素杆病理学可以引发突触损失，已在啮齿动物神经元、海马切片和人类神经退行性疾病（如阿尔茨海默氏病（AD））的体内小鼠模型中进行了广泛研究。在这些系统中，由疾病相关因素（例如 AD 中的可溶性淀粉样蛋白-β (Aβ) 寡聚物）诱导的视杆细胞形成，利用了需要细胞朊病毒蛋白 (PrPC)、NADPH 氧化酶 (NOX) 和细胞因子/趋化因子受体（CCR5 和/或 CXCR4）的途径。然而，尚未在人类神经元模型中系统地评估杆状通路。在这里，我们表征了从人诱导多能干细胞 (iPSC) 分化而来的谷氨酸能神经元，这些神经元响应 PrPC 依赖性途径的激活剂而形成杆状细胞。基质、细胞密度的优化和神经胶质条件培养基的使用产生了一个强大的系统，用于在没有神经胶质细胞的情况下研究 Aβ 诱导的杆的发育，这表明细胞自主途径。年轻神经元中的视杆细胞诱导需要 PrPC 的异位表达，但这种依赖性在第 55 天时消失。视杆细胞诱导途径中蛋白质的定量表明，PrPC 和 CXCR4 表达增加可能是第 35 天和第 55 天之间视杆细胞对 Aβ 的反应加倍的因素。FDA 批准的 CXCR4 和 CCR5 拮抗剂可抑制视杆细胞反应。杆状体主要在树突中观察到，尽管严重的细胞骨架破坏阻止了超过 40% 的杆状体分配给轴突或树突。在缺乏神经胶质细胞的情况下（在这种情况下，更容易观察到杆状细胞），神经元会成熟并激发动作电位，但不会形成功能性突触。然而，含有 PSD95 的树突棘与含有谷氨酸转运蛋白 VGLUT1 的突触前囊泡的轴突区域相关。因此，我们的结果确定干细胞源性神经元作为研究人类细胞环境中辅丝乳素杆状体形成的稳健模型，并用于开发有效的治疗策略来治疗由不同杆状体引发剂的多种蛋白质病引起的痴呆。
Cofilactin rod pathology, which can initiate synapse loss, has been extensively studied in rodent neurons, hippocampal slices, and in vivo mouse models of human neurodegenerative diseases such as Alzheimer’s disease (AD). In these systems, rod formation induced by disease-associated factors, such as soluble oligomers of Amyloid-β (Aβ) in AD, utilizes a pathway requiring cellular prion protein (PrPC), NADPH oxidase (NOX), and cytokine/chemokine receptors (CCR5 and/or CXCR4). However, rod pathways have not been systematically assessed in a human neuronal model. Here, we characterize glutamatergic neurons differentiated from human-induced pluripotent stem cells (iPSCs) for the formation of rods in response to activators of the PrPC-dependent pathway. Optimization of substratum, cell density, and use of glial-conditioned medium yielded a robust system for studying the development of Aβ-induced rods in the absence of glia, suggesting a cell-autonomous pathway. Rod induction in younger neurons requires ectopic expression of PrPC, but this dependency disappears by Day 55. The quantification of proteins within the rod-inducing pathway suggests that increased PrPC and CXCR4 expression may be factors in the doubling of the rod response to Aβ between Days 35 and 55. FDA-approved antagonists to CXCR4 and CCR5 inhibit the rod response. Rods were predominantly observed in dendrites, although severe cytoskeletal disruptions prevented the assignment of over 40% of the rods to either an axon or dendrite. In the absence of glia, a condition in which rods are more readily observed, neurons mature and fire action potentials but do not form functional synapses. However, PSD95-containing dendritic spines associate with axonal regions of pre-synaptic vesicles containing the glutamate transporter, VGLUT1. Thus, our results identified stem cell-derived neurons as a robust model for studying cofilactin rod formation in a human cellular environment and for developing effective therapeutic strategies for the treatment of dementias arising from multiple proteinopathies with different rod initiators.
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抗炎化合物在人类免疫缺陷病毒 1 糖蛋白 120 介导的脑炎症中的作用。
影响因子：
9.3
作者：
Ashraf T;Jiang W;Hoque MT;Henderson J;Wu C;Bendayan R
通讯作者：
Bendayan R
影响因子：
25
作者：
Gu, Jiaping;Lee, Chi Wai;Fan, Yanjie;Komlos, Daniel;Tang, Xin;Sun, Chicheng;Yu, Kuai;Hartzell, H. Criss;Chen, Gong;Bamburg, James R.;Zheng, James Q.
通讯作者：
Zheng, James Q.
通过从头合成神经递质来诱导突触形成。
影响因子：
16.6
作者：
通讯作者：
--
DOI：
10.1002/cm.21282
发表时间：
2016-09
期刊：
Cytoskeleton (Hoboken, N.J.)
影响因子：
--
作者：
Bamburg JR;Bernstein BW
通讯作者：
Bernstein BW
影响因子：
25
作者：
Cleary, JP;Walsh, DM;Ashe, KH
通讯作者：
Ashe, KH