Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations.
Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations.
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DOI：
10.1016/j.celrep.2016.09.034
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发表时间：
2016-10-11
期刊：
影响因子：
8.8
通讯作者：
Goldstein LS
中科院分区：
文献类型：
--
作者：
Woodruff G;Reyna SM;Dunlap M;Van Der Kant R;Callender JA;Young JE;Roberts EA;Goldstein LS
我们研究了家族性阿尔茨海默病（fAD）突变在人类ipsc来源的神经元中引起的早期表型。利用基因组编辑技术在内源性位点对携带fAD PS1或APP突变的神经元进行分析，发现fAD突变神经元在APP和脂蛋白的内吞作用和体细胞到轴突转胞吞的循环状态中存在以前未报道的缺陷。通过β-分泌酶抑制剂的治疗，胞吞的减少可以恢复。我们的数据表明，APP的β-CTF片段的积累，而不是Aβ的积累，减缓了内吞循环室中以转胞GTPase Rab11为标志的囊泡形成。我们证实了先前的结果，即内吞作用在AD中受到影响，并扩展这些结果以发现神经元特异性缺陷。脂蛋白内吞作用和轴突胞吞作用的减少表明，脂蛋白和其他关键物质的内吞轴突传递的神经元特异性损伤可能会损害fAD的突触维持。Woodruff等发现FAD突变神经元表现出由Rab11介导的APP和脂蛋白的异常内吞和胞吞。有缺陷的脂蛋白内吞作用和胞吞作用可通过β-分泌酶抑制来挽救。
We investigated early phenotypes caused by familial Alzheimer’s Disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTF fragments of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11. We confirm previous results that endocytosis is affected in AD, and extend these to uncover a neuron-specific defect. Decreased lipoprotein endocytosis and transcytosis to the axon suggests that a neuron-specific impairment in endocytic axonal delivery of lipoproteins and other key materials might compromise synaptic maintenance in fAD. Woodruff et al find that FAD mutant neurons display abnormal endocytosis and transcytosis of APP and lipoproteins that is mediated by Rab11. Defective endocytosis and transcytosis of lipoproteins is rescued by β-secretase inhibition.
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