Accumulation of murine amyloidβ42 in a gene-dosage-dependent manner in PS1 'knock-in' mice
Accumulation of murine amyloidβ42 in a gene-dosage-dependent manner in PS1 'knock-in' mice
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DOI：
10.1046/j.1460-9568.1999.00698.x
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发表时间：
1999-07-01
影响因子：
3.4
通讯作者：
Takeda, M
中科院分区：
文献类型：
--
作者：
Nakano, Y;Kondoh, G;Takeda, M
早老素-1（PS1）错义突变动物模型的建立是了解家族性阿尔茨海默病（FAD）分子发病机制和开发该疾病治疗策略的第一步。我们先前描述了一个患有由PS1的I213 T突变引起的FAD的日本家族，其中在45 +/-4.2岁时观察到阿尔茨海默病的典型体征和症状[哈代，J.（1997）Trends.神经科学，20，154-159; Kamino，K.等人（1996）Neurosci.信件：208，195-198]。在这里，我们报告的建立'敲入'小鼠与I213 T PS1错义突变。北方印迹和逆转录聚合酶链反应（RT-PCR）分析表明，突变的PS1等位基因的表达水平与内源性PS1等位基因相同，表明PS1错义突变被成功引入小鼠PS1基因座，因此，这种情况模拟了携带PS1错义突变的FAD患者。淀粉样β（A β）42（43）肽，而不是A β 40肽，在16-20周龄的“基因敲入”小鼠中积累。在“基因敲入”小鼠中观察到A β 42（43）增加的明显基因剂量效应：两个等位基因突变的小鼠中A β 42（43）的百分比增加是单一等位基因小鼠的两倍。这些结果表明，突变的PS1基因表达水平可能与高度淀粉样蛋白A β 42的产生密切相关（43），并证实PS1突变对淀粉样前体蛋白（APP）加工具有重要影响，与突变基因的表达水平成比例。
The establishment of an animal model with a missense mutation of presenilin-1 (PS1) is an initial step toward understanding the molecular pathogenesis of familial Alzheimer's disease (FAD) and developing therapeutic strategies for the disease. We previously described a Japanese family with FAD caused by the I213T mutation of PS1, in which typical signs and symptoms of Alzheimer's disease were observed at the age of 45 +/- 4.2 years [Hardy, J. (1997) Trends. Neurosci., 20, 154-159; Kamino, K. et al. (1996) Neurosci. Lett., 208, 195-198]. Here, we report the establishment of 'knock-in' mice with the I213T PS1 missense mutation. Northern blot and reverse transcription polymerase chain reaction (RT-PCR) analyses showed that the mutated PS1 allele was expressed at the same level as the endogenous PS1 allele, demonstrating that the PS1 missense mutation was successfully introduced into the mouse PS1 locus, and therefore that the situation mimics that in FAD patients bearing PS1 missense mutations. Amyloid beta (A beta) 42(43) peptide, but not A beta 40 peptide, accumulated in 'knock-in' mice at the age of 16-20 weeks. A clear gene-dosage effect on the increase of A beta 42(43) was observed in 'knock-in' mice: the percentage increase of A beta 42(43) in mice with mutations in both alleles was twice as high as that in mice with a single allele. These results indicate that the level of the mutated PS1 gene expression is likely to be critically involved in the production of highly amyloidogenic A beta 42(43), and confirm that PS1 mutation has an important effect on amyloid precursor protein (APP) processing, in proportion to the level of the expression of the mutant gene.