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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Mutant ubiquitin decreases amyloid β plaque formation in a transgenic mouse model of Alzheimer's disease
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Mutant ubiquitin decreases amyloid β plaque formation in a transgenic mouse model of Alzheimer's disease

机译：突变泛素减少阿尔茨海默氏病转基因小鼠模型中淀粉样蛋白β斑块的形成

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摘要

The mutant ubiquitin UBB +1 is a substrate as well as an inhibitor of the ubiquitin-proteasome system (UPS) and accumulates in the neuropathological hallmarks of Alzheimer's disease (AD). A role for the UPS has been suggested in the generation of amyloid β (Aβ) plaques in AD. To investigate the effect of UBB +1 expression on amyloid pathology in vivo, we crossed UBB +1 transgenic mice with a transgenic line expressing AD-associated mutant amyloid precursor protein (APPSwe) and mutant presenilin 1 (PS1dE9), resulting in APPPS1/UBB +1 triple transgenic mice. In these mice, we determined the Aβ levels at 3, 6, 9 and 11 months of age. Surprisingly, we found a significant decrease in Aβ deposition in amyloid plaques and levels of soluble Aβ 42 in APPPS1/UBB +1 transgenic mice compared to APPPS1 mice at 6 months of age, without alterations in UBB +1 protein levels or proteasomal chymotrypsin activity. These lowering effects of UBB +1 on Aβ deposition were transient, as this relative decrease in plaque load was not significant in APPPS1/UBB +1 mice at 9 and 11 months of age. We also show that APPPS1/UBB +1 mice exhibit astrogliosis, indicating that they may not be improved functionally compared to APPPS1 mice despite the Aβ reduction. The molecular mechanism underlying this decrease in Aβ deposition in APPPS1/UBB +1 mice is more complex than previously assumed because UBB +1 is also ubiquitinated at K63 opening the possibility of additional effects of UBB +1 (e.g. kinase activation).
机译：突变型泛素UBB +1是泛素-蛋白酶体系统（UPS）的底物和抑制剂，并在阿尔茨海默氏病（AD）的神经病理学特征中积累。已经提出UPS的作用是在AD中淀粉样β（Aβ）斑块的产生中。为了研究UBB +1表达对体内淀粉样蛋白病理学的影响，我们将UBB +1转基因小鼠与表达AD相关突变淀粉样蛋白前体蛋白（APPSwe）和早老素1突变体（PS1dE9）的转基因品系杂交，得到APPPS1 / UBB +1三联转基因小鼠。在这些小鼠中，我们确定了3、6、9和11个月大时的Aβ水平。出乎意料的是，我们发现与6个月大的APPPS1小鼠相比，APPPS1 / UBB +1转基因小鼠的淀粉样斑块中Aβ沉积和可溶性Aβ42水平显着降低，而UBB +1蛋白水平或蛋白酶体胰凝乳蛋白酶活性没有改变。这些UBB +1降低Aβ沉积的作用是短暂的，因为在9和11个月大时APPPS1 / UBB +1小鼠的噬斑负荷相对降低并不明显。我们还显示，APPPS1 / UBB +1小鼠表现出星形胶质增生，表明尽管Aβ降低，与APPPS1小鼠相比它们可能无法改善功能。在APPPS1 / UBB +1小鼠中这种Aβ沉积减少的分子机制比以前设想的更为复杂，因为UBB +1在K63处也被泛素化，从而可能增加UBB +1的其他作用（例如激酶激活）。

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