A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ
A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ
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DOI：
10.1016/j.neuron.2019.07.010
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发表时间：
2019-10-23
期刊：
影响因子：
16.2
通讯作者：
Tessier-Lavigne, Marc
中科院分区：
文献类型：
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作者：
Kwart, Dylan;Gregg, Andrew;Tessier-Lavigne, Marc
家族性阿尔茨海默病（fAD）是由淀粉样前体蛋白（APP）和早老素（PSEN 1和PSEN 2）基因突变引起的。在这里，我们利用诱导多能干细胞（iPSC）和CRISPR/Cas9基因组编辑技术的最新进展，产生了一组携带APP和/或PSEN 1突变的同基因敲入人类iPSC系。全球转录组学和翻译组学分析显示，fAD突变对AD相关和内吞相关基因的表达具有重叠效应。突变神经元也增加Rab 5+早期内体大小。APP和PSEN 1突变对Ab产生的影响不一致，但对APP β C-末端片段（β-CTF）的影响相似，这些片段在所有突变神经元中积累。重要的是，内体功能障碍与β-CTFs的积累相关，而不是Ab，并且可以通过β-分泌酶（BACE）的药理学调节来挽救。这些数据显示了我们的突变iPSC在非过表达人类系统中研究AD相关表型的效用，并支持越来越多的证据表明β-CTF可能在AD发病机制中至关重要。
Familial Alzheimer's disease (fAD) results from mutations in the amyloid precursor protein (APP) and presenilin (PSEN1 and PSEN2) genes. Here we leveraged recent advances in induced pluripotent stem cell (iPSC) and CRISPR/Cas9 genome editing technologies to generate a panel of isogenic knockin human iPSC lines carrying APP and/or PSEN1 mutations. Global transcriptomic and translatomic profiling revealed that fAD mutations have overlapping effects on the expression of AD-related and endocytosis-associated genes. Mutant neurons also increased Rab5+ early endosome size. APP and PSEN1 mutations had discordant effects on Ab production but similar effects on APP beta C-terminal fragments (beta-CTFs), which accumulate in all mutant neurons. Importantly, endosomal dysfunction correlated with accumulation of beta-CTFs, not Ab, and could be rescued by pharmacological modulation of beta-secretase (BACE). These data display the utility of our mutant iPSCs in studying AD-related phenotypes in a non-overexpression human-based system and support mounting evidence that beta-CTF may be critical in AD pathogenesis.