Amyloid precursor protein-mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration
Amyloid precursor protein-mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration
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DOI：
10.1172/jci82409
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发表时间：
2016-05-01
影响因子：
15.9
通讯作者：
Wu, Chengbiao
中科院分区：
文献类型：
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作者：
Xu, Wei;Weissmiller, April M.;Wu, Chengbiao
内体/溶酶体途径在阿尔茨海默病（AD）和唐氏综合征（DS）的病程早期被破坏;然而，尚不清楚该途径中的功能障碍如何影响这些疾病的发展。在此，我们探讨了内体功能障碍导致AD和DS发病的细胞和分子机制。我们确定全长淀粉样前体蛋白（APP）及其β-C-末端片段（β-CTF）通过Rab 5的激活增加而起作用，导致早期内体扩大并破坏神经生长因子（NGF）信号的逆行轴突运输。APP及其各种产品的功能影响进行了研究，在PC 12细胞，培养大鼠基底前脑胆碱能神经元（BFCN），和BFCN从DS小鼠模型。我们发现，全长野生型APP（APP（WT））和β-CTF都诱导内体扩大和破坏NGF信号和轴突运输。单独的β-CTF诱导BFCN萎缩，其被显性阴性Rab 5突变体Rab 5（S34 N）挽救。此外，显性负Rab 5结构的表达显着减少APP诱导的果蝇轴突阻滞。因此，增加的APP和/或β-CTF影响内吞途径以破坏NGF运输和信号传导，导致BFCN中的营养缺陷。我们的数据有力地支持了Rab 5活性失调对AD和DS的早期发病机制有重要作用的新概念。
The endosome/lysosome pathway is disrupted early in the course of both Alzheimer's disease (AD) and Down syndrome (DS); however, it is not clear how dysfunction in this pathway influences the development of these diseases. Herein, we explored the cellular and molecular mechanisms by which endosomal dysfunction contributes to the pathogenesis of AD and DS. We determined that full-length amyloid precursor protein (APP) and its beta-C-terminal fragment (beta-CTF) act though increased activation of Rab5 to cause enlargement of early endosomes and to disrupt retrograde axonal trafficking of nerve growth factor (NGF) signals. The functional impacts of APP and its various products were investigated in PC12 cells, cultured rat basal forebrain cholinergic neurons (BFCNs), and BFCNs from a mouse model of DS. We found that the full-length wild-type APP (APP(WT)) and beta-CTF both induced endosomal enlargement and disrupted NGF signaling and axonal trafficking. beta-CTF alone induced atrophy of BFCNs that was rescued by the dominant-negative Rab5 mutant, Rab5(S34N). Moreover, expression of a dominant-negative Rab5 construct markedly reduced APP-induced axonal blockage in Drosophila. Therefore, increased APP and/or beta-CTF impact the endocytic pathway to disrupt NGF trafficking and signaling, resulting in trophic deficits in BFCNs. Our data strongly support the emerging concept that dysregulation of Rab5 activity contributes importantly to early pathogenesis of AD and DS.