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首页> 外文期刊>The European Journal of Neuroscience >Decreased axonal transport rates in the Tg2576 APP transgenic mouse: Improvement with the gamma-secretase inhibitor MRK-560 as detected by manganese-enhanced MRI
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Decreased axonal transport rates in the Tg2576 APP transgenic mouse: Improvement with the gamma-secretase inhibitor MRK-560 as detected by manganese-enhanced MRI

机译：Tg2576 APP转基因小鼠的轴突运输速率降低：锰增强MRI检测发现，γ-分泌酶抑制剂MRK-560有所改善

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摘要

Neuropil deposition of beta-amyloid (Aβ) peptides is believed to be a key event in the neurodegenerative process of Alzheimer's disease (AD). An early and consistent clinical finding in AD is olfactory dysfunction with associated pathology. Interestingly, transgenic amyloid precursor protein (Tg2576) mice also show early amyloid pathology in olfactory regions. Moreover, a recent study indicates that axonal transport is compromised in the olfactory system of Tg2576 mice, as measured by manganese-enhanced magnetic resonance imaging (MEMRI). Here we tested whether the putative axonal transport deficit in the Tg2576 mouse model improves in response to a selective gamma-secretase inhibitor, N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560). Tg2576 mice or wild-type (WT) littermates were treated daily with MRK-560 (30μmol/kg) or vehicle for 4 (acute) or 29days (chronic). The subsequent MEMRI analysis revealed a distinct axonal transport dysfunction in the Tg2576 mice compared with its littermate controls. Interestingly, the impairment of axonal transport could be fully reversed by chronic administration of MRK-560, in line with the significantly lowered levels of both soluble and insoluble forms of Aβ found in the brain and olfactory bulbs (OBs) following treatment. However, no improvement of axonal transport was observed after acute treatment with MRK-560, where soluble but not insoluble forms of Aβ were reduced in the brain and OBs. The present results show that axonal transport is impaired in Tg2576 mice compared with WT controls, as measured by MEMRI. Chronic treatment in vivo with a gamma-secretase inhibitor, MRK-560, significantly reduces soluble and insoluble forms of Aβ, and fully reverses the axonal transport dysfunction.
机译：β-淀粉样蛋白（Aβ）肽的神经纤维沉积被认为是阿尔茨海默氏病（AD）神经变性过程中的关键事件。 AD的早期且一致的临床发现是嗅觉功能障碍以及相关的病理。有趣的是，转基因淀粉样蛋白前体蛋白（Tg2576）小鼠在嗅觉区域也显示出早期淀粉样蛋白病理。此外，最近的研究表明，如通过锰增强磁共振成像（MEMRI）所测量的，Tg2576小鼠的嗅觉系统中轴突运输受到损害。在这里，我们测试了Tg2576小鼠模型中假定的轴突运输缺陷是否会响应选择性的γ-分泌酶抑制剂N- [cis-4-[（4-氯苯基）-磺酰基] -4-（2,5-二氟苯基）而改善环己基] -1,1,1-三氟甲磺酰胺（MRK-560）。每天用MRK-560（30μmol/ kg）或溶媒治疗Tg2576小鼠或野生型（WT）同窝仔4天（急性）或29天（慢性）。随后的MEMRI分析显示，与同窝对照相比，Tg2576小鼠有明显的轴突运输功能障碍。有趣的是，通过长期施用MRK-560可以完全逆转轴突运输的损伤，这与治疗后大脑和嗅球（OB）中发现的可溶性和不溶性Aβ含量显着降低相符。然而，在用MRK-560进行急性治疗后，未观察到轴突运输的改善，其中可溶但非不可溶形式的Aβ在大脑和OB中减少了。目前的结果表明，与WT对照相比，Tg2576小鼠的轴突运输受到损害，这是通过MEMRI测量的。用γ-分泌酶抑制剂MRK-560在体内进行的慢性治疗可显着减少Aβ的可溶和不可溶形式，并完全逆转轴突运输功能障碍。

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