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首页> 外文期刊>Neuron >Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.
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Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.

机译：唐氏综合征小鼠模型中App表达的增加破坏了NGF的运输，并导致胆碱能神经元变性。

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Degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive dysfunction in Alzheimer's disease (AD) and Down's syndrome (DS). We used Ts65Dn and Ts1Cje mouse models of DS to show that the increased dose of the amyloid precursor protein gene, App, acts to markedly decrease NGF retrograde transport and cause degeneration of BFCNs. NGF transport was also decreased in mice expressing wild-type human APP or a familial AD-linked mutant APP; while significant, the decreases were less marked and there was no evident degeneration of BFCNs. Because of evidence suggesting that the NGF transport defect was intra-axonal, we explored within cholinergic axons the status of early endosomes (EEs). NGF-containing EEs were enlarged in Ts65Dn mice and their App content was increased. Our study thus provides evidence for a pathogenic mechanism for DS in which increased expression of App, in the context of trisomy, causes abnormal transport of NGF and cholinergic neurodegeneration.
机译：基底前脑胆碱能神经元（BFCNs）的变性会导致阿尔茨海默氏病（AD）和唐氏综合症（DS）的认知功能障碍。我们使用DS的Ts65Dn和Ts1Cje小鼠模型来证明增加剂量的淀粉样蛋白前体蛋白基因App可以显着降低NGF逆行转运并引起BFCNs变性。在表达野生型人APP或家族性AD关联突变APP的小鼠中，NGF的转运也降低了。虽然显着，但下降幅度较小，并且没有明显的BFCN变性。因为有证据表明NGF转运缺陷是轴突内的，所以我们在胆碱能轴突内探讨了早期内体（EEs）的状态。在Ts65Dn小鼠中，含有NGF的EE扩大，其App含量增加。因此，我们的研究为DS的致病机制提供了证据，其中在三体性的背景下，App表达的增加导致NGF的异常转运和胆碱能神经退行性变。

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