Herzig Martin C, Paganetti Paolo, Staufenbiel Matthias, Jucker Mathias
Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Neurodegener Dis. 2007;4(2-3):127-35. doi: 10.1159/000101837.
APPDutch transgenic (tg) mice develop cerebral amyloid angiopathy (CAA) that consists mainly of AbetaDutch40, with virtually no parenchymal amyloid plaques. To modulate cerebral amyloidosis, we crossbred APPDutch mice with either BACE1 tg mice to increase total AbetaDutch, or with G384A-mutated PS1 tg mice to elevate the ratio of AbetaDutch42 to AbetaDutch40. We analyzed all mice at 22 months of age. Compared to APPDutch mice, double-tg APPDutch/BACE1 mice revealed increased CAA mainly due to extensive vascular amyloid accumulation in the thalamus. In addition, they developed parenchymal amyloid in cortex and subiculum. In contrast, APPDutch/G384A-PS1 mice showed extensive, predominantly parenchymal amyloid throughout the entire brain, interestingly, even in the thalamus. The amyloid, composed largely of AbetaDutch42, was different compared to that in APPDutch/BACE1 mice which was composed mainly of AbetaDutch40. In summary, these mouse models reveal a broad variety and region-specificity of parenchymal versus vascular cerebral amyloid. This is partially explained by the absolute amount of neuronally produced AbetaDutch42 and AbetaDutch40 and ratio between the two. We conclude that the absolute levels of Abeta in combination with the ratio of Abeta42 to Abeta40 play a key role in determining the cerebral compartment and brain region in which Abeta is deposited.
携带荷兰型淀粉样前体蛋白（APPDutch）的转基因（tg）小鼠会发生脑淀粉样血管病（CAA），主要由AbetaDutch40组成，几乎没有实质淀粉样斑块。为了调节脑淀粉样变性，我们将APPDutch小鼠与BACE1转基因小鼠杂交以增加总的AbetaDutch，或者与G384A突变的PS1转基因小鼠杂交以提高AbetaDutch42与AbetaDutch40的比例。我们在22个月龄时分析了所有小鼠。与APPDutch小鼠相比，双转基因APPDutch/BACE1小鼠的CAA增加，主要是由于丘脑广泛的血管淀粉样蛋白积聚。此外，它们在皮质和海马下托出现了实质淀粉样变。相比之下，APPDutch/G384A-PS1小鼠在整个大脑中显示出广泛的、主要是实质淀粉样变，有趣的是，甚至在丘脑中也是如此。这种淀粉样蛋白主要由AbetaDutch42组成，与主要由AbetaDutch40组成的APPDutch/BACE1小鼠中的淀粉样蛋白不同。总之，这些小鼠模型揭示了实质与血管脑淀粉样变的广泛多样性和区域特异性。这部分可以通过神经元产生的AbetaDutch42和AbetaDutch40的绝对量以及两者之间的比例来解释。我们得出结论，Abeta的绝对水平与Abeta42与Abeta40的比例在决定Abeta沉积的脑区室和脑区中起关键作用。
