Andrä K, Abramowski D, Duke M, Probst A, Wiederhold K H, Bürki K, Goedert M, Sommer B, Staufenbiel M
Preclinical Research, Sandoz Pharma Ltd, Basel, Switzerland.
Neurobiol Aging. 1996 Mar-Apr;17(2):183-90. doi: 10.1016/0197-4580(95)02066-7.
The beta-amyloid precursor protein (APP) carries mutations in codons 717 or 670/671, which cosegregate with familial forms of Alzheimer's disease (AD). As an initial step to study the related pathogenetic mechanisms in vivo we have generated transgenic mice expressing APP with these mutations. Several neuron-specific promoters were used to drive expression of human APP cDNAs. Only the Thy-1 promoter yielded transgene expression levels comparable to or above the endogenous mouse levels. Deletion of a 121 bp sequence from the 3' untranslated region of APP appeared to increase mRNA levels. Transgene mRNA was found throughout the brain with highest levels in hippocampus and cerebral cortex. Accordingly, human APP was detected in these regions by Western blotting. Protein levels paralleled mRNA levels reaching or exceeding the amount of endogenous APP. Variable reactivity of human APP in cell bodies was shown by immunocytochemistry. Although our initial histological examinations did not reveal any alterations characteristic of AD, further studied will be required.
β-淀粉样前体蛋白（APP）在密码子717或670/671处携带突变，这些突变与家族性阿尔茨海默病（AD）共分离。作为在体内研究相关致病机制的第一步，我们培育了表达带有这些突变的APP的转基因小鼠。使用了几种神经元特异性启动子来驱动人APP cDNA的表达。只有Thy-1启动子产生的转基因表达水平与内源性小鼠水平相当或高于内源性小鼠水平。从APP的3'非翻译区缺失121 bp序列似乎会增加mRNA水平。在整个大脑中都发现了转基因mRNA，在海马体和大脑皮层中水平最高。因此，通过蛋白质印迹法在这些区域检测到了人APP。蛋白质水平与mRNA水平平行，达到或超过内源性APP的量。免疫细胞化学显示人APP在细胞体中的反应性可变。尽管我们最初的组织学检查没有发现任何AD特有的改变，但仍需要进一步研究。
