Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein.
Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein.
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DOI：
10.1016/j.stemcr.2018.01.031
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发表时间：
2018-03-13
影响因子：
5.9
通讯作者：
Goldstein LSB
中科院分区：
文献类型：
--
作者：
Young JE;Fong LK;Frankowski H;Petsko GA;Small SA;Goldstein LSB
由于人类群体的遗传和环境异质性以及现有动物模型的局限性，开发有效的治疗方法对晚发型散发性阿尔茨海默病（SAD）等复杂疾病很困难。在这里，我们使用hipsc衍生的神经元来测试一种稳定逆转录物的化合物，逆转录物是一种高度保守的多蛋白组合，在通过内体网络运输分子中起关键作用。使用这种人类特异性系统，我们已经证实了先前在小鼠模型中产生的数据，并表明逆转录稳定对人类干细胞来源的神经元产生淀粉样蛋白具有潜在的有益作用。我们进一步证明，神经元内逆转录复合物水平的操纵以淀粉样蛋白不依赖的方式影响致病性TAU磷酸化。综上所述，我们的工作表明，逆转录物稳定是阿尔茨海默病治疗开发的一个有希望的候选药物，并突出了在人类特异性神经系统中测试新化合物的优势。反转录稳定分子降低了SAD和FAD细胞系中Aβ和磷酸化tau的水平反转录稳定分子以app不依赖的方式降低了tau磷酸化，证实了小鼠的研究，并突出了hiPSCs作为临床前模型的作用。在这项工作中，Young和同事测试了在人类神经元模型中，一个大的内噬运输复合物，即反转录物组装的稳定如何降低细胞AD表型。使用患者来源和基因组编辑的hipsc，他们表明，逆转录功能的增强分别影响APP加工和tau磷酸化。
Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer’s disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons. We further demonstrate that manipulation of retromer complex levels within neurons affects pathogenic TAU phosphorylation in an amyloid-independent manner. Taken together, our work demonstrates that retromer stabilization is a promising candidate for therapeutic development in AD and highlights the advantages of testing novel compounds in a human-specific, neuronal system. A retromer stabilizing molecule reduces Aβ and phospho-TAU levels in human neurons The molecule reduces Aβ and pTau in both SAD and FAD cell lines Retromer stabilization reduces tau phosphorylation in an APP-independent manner Confirms studies in mice and highlights hiPSCs as a preclinical model In this work, Young and colleagues test how stabilization of a large endocytic trafficking complex, the retromer assembly, reduces cellular AD phenotypes in a human neuronal model. Using both patient-derived and genome-edited hiPSCs, they show that enhancement of retromer function affects both APP processing and tau phosphorylation independently.
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