Van Broeck Bianca, Vanhoutte Greet, Cuijt Ivy, Pereson Sandra, Joris Geert, Timmermans Jean-Pierre, Van der Linden Annemie, Van Broeckhoven Christine, Kumar-Singh Samir
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
Neurosci Lett. 2008 Dec 12;447(2-3):143-7. doi: 10.1016/j.neulet.2008.09.073. Epub 2008 Oct 1.
We previously described two transgenic mouse lines expressing sub-endogenous levels of the 'Austrian' APP-T714I mutation (driven by the prenatally active PDGF-beta promoter; APP-Au mice) and showing intraneuronal Abeta pathology and reduced brain volumes on MRI at 12 and 20 months of age. To further investigate whether reduced brain sizes were caused by neurodegeneration or a neurodevelopmental defect, we now measured brain volumes as early as postnatal day 10. At this age, a distinguishable reduction in brain volumes was absent, indicating that brain volume deficits in APP-Au mice are not caused by a neurodevelopmental defect. To further study the association between intraneuronal Abeta and reduced brain volumes, we further generated and analyzed an APP transgenic mouse model expressing both Austrian and Swedish (K670N/M671L) mutations (APP-SwAu mice). APP-Swedish mutation is known to lead to altered APP processing in the secretory pathway, precluding its later processing in endosomal-lysosomal compartments, the site of intraneuronal Abeta accumulation. Also, to have higher levels of transgene expression only after birth, a murine Thy-1 promoter was utilized for APP-SwAu mouse lines. Despite having five times higher transgene APP levels compared to APP-Au mice, APP-SwAu mice showed significantly lower intraneuronal Abeta levels in the absence of reduced brain volumes, suggesting that intraneuronal Abeta accumulation is related to reduced brain volumes in APP-Au mice. These data also provide a first in vivo indication of altered processing of APP-Swedish at sub-endogenous levels, an effect not observed in mouse models expressing the APP-Swedish mutation in high amounts.
我们之前描述了两种转基因小鼠品系，它们表达低于内源性水平的“Austrian”APP-T714I突变（由产前活跃的血小板衍生生长因子β启动子驱动；APP-Au小鼠），并在12和20月龄时在MRI上显示出神经元内淀粉样β蛋白病理学特征以及脑容量减小。为了进一步研究脑容量减小是由神经退行性变还是神经发育缺陷引起的，我们现在早在出生后第10天就测量了脑容量。在这个年龄，没有明显的脑容量减小，这表明APP-Au小鼠的脑容量缺陷不是由神经发育缺陷引起的。为了进一步研究神经元内淀粉样β蛋白与脑容量减小之间的关联，我们进一步构建并分析了一种表达Austrian和Swedish（K670N/M671L）突变的APP转基因小鼠模型（APP-SwAu小鼠）。已知APP-Swedish突变会导致分泌途径中APP加工改变，从而阻止其在内体-溶酶体区室（神经元内淀粉样β蛋白积累的部位）的后续加工。此外，为了仅在出生后才有更高水平的转基因表达，APP-SwAu小鼠品系使用了鼠Thy-1启动子。尽管与APP-Au小鼠相比，APP-SwAu小鼠的转基因APP水平高出五倍，但在脑容量没有减小的情况下，APP-SwAu小鼠的神经元内淀粉样β蛋白水平显著降低，这表明神经元内淀粉样β蛋白积累与APP-Au小鼠的脑容量减小有关。这些数据还首次在体内表明，内源性水平以下的APP-Swedish加工发生了改变，这种效应在大量表达APP-Swedish突变的小鼠模型中未观察到。
