Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology
Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology
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DOI：
10.1073/pnas.94.24.13287
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发表时间：
1997-11-25
影响因子：
11.1
通讯作者：
Sommer, B
中科院分区：
文献类型：
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作者：
SturchlerPierrat, C;Abramowski, D;Sommer, B
淀粉样前体蛋白 (APP) 基因突变通过影响淀粉样β (Aβ) 肽（AD 斑块的主要成分）的形成而导致早发性家族性阿尔茨海默病 (AD)。我们在转基因小鼠的大脑中表达了含有这些突变的人 APP(751)。两种转基因小鼠品系出现了让人想起 AD 的病理特征，病理程度取决于表达水平和特定突变。 670/671位瑞典双突变的人APP与V717I突变的2倍过表达导致18月龄转基因小鼠新皮质和海马中Aβ沉积，沉积物多为弥漫型；然而，可以检测到一些嗜刚果红斑块。在仅携带瑞典突变的人类 APP 7 倍过度表达的小鼠中，典型的斑块在 6 个月时出现，随着年龄的增长而增加，并且在首次检测时呈刚果红阳性，这些嗜刚果红斑块伴有神经炎变化和营养不良的胆碱能纤维，此外，由大量神经胶质反应表明的炎症过程是明显的，最值得注意的是，斑块对过度磷酸化 tau 具有免疫反应性，让人想起早期 tau 病理学，免疫反应性仅存在于两个细胞系的嗜刚果红性老年斑中。在表达较高的细胞系中，6 个月大的动物中生化显示 tau 磷酸化水平升高，并随着年龄的增长而增加。这些小鼠与 AD 病理学的主要特征相似，表明 Aβ 在该疾病的发病机制中发挥着核心作用。
Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid beta (A beta) peptide, the major constituent of AD plaques, We expressed human APP(751) containing these mutations in the brains of transgenic mice, Two transgenic mouse lines develop pathological features reminiscent of AD, The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670/671 combined with the V717I mutation causes A beta deposition in neocortex and hippocampus of 18-month-old transgenic mice, The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection, These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers, Furthermore, inflammatory processes indicated by a massive glial reaction are apparent, Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology, The immunoreactivity is exclusively found in congophilic senile plaques of both lines, In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age, These mice resemble major features of AD pathology and suggest a central role of A beta in the pathogenesis of the disease.