Targeted introduction of V642I mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer's disease in aged mice
Targeted introduction of V642I mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer's disease in aged mice
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DOI：
10.1111/j.0953-816x.2004.03397.x
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发表时间：
2004-05-01
影响因子：
3.4
通讯作者：
Kouyama, K
中科院分区：
文献类型：
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作者：
Kawasumi, M;Chiba, T;Kouyama, K
虽然阿尔茨海默病（AD）的确切病因尚不清楚，但已在罕见的家族性AD（FAD）病例中发现了不同的基因突变。淀粉样前体蛋白（APP）V642 I突变与FAD共分离，具有完美的穿透性，并且具有该突变的患者的临床病理特征类似于散发性AD。为了研究体内这种FAD连锁性状的致病过程，我们使用同源重组和Cre-loxP位点特异性重组（“敲入”技术）产生了APP基因中具有相应点突变的小鼠。具有杂合V642 I-APP等位基因的小鼠最精确地反映了携带该突变的人类的基因型。在2.5年的观察期内，突变体与野生型同窝仔明显无法区分。然而，行为分析显示显着恶化的长期记忆的突变体时，检查保留的空间注意力。有趣的是，空间记忆的获得受到轻微影响，但短期工作记忆根本没有恶化。组织学检查显示神经炎斑或神经纤维缠结形成阴性，而在突变脑匀浆中，较长形式的β-淀粉样蛋白A β 42（43）相对于较短形式（A β 40）的相对量显著增加。我们得出结论，V642 I-APP突变等位基因在老年小鼠赋予功能组件，但不是有机组件，AD相关的表型，在AD的早期阶段观察到。该V642 I-APP基因敲入突变株可作为研究AD早期体内致病过程和开发该阶段治疗药物的模型。
While the exact aetiology of Alzheimer's disease (AD) is unknown, distinct genetic mutations have been identified for the rare cases of familial AD (FAD). V642I mutation in amyloid precursor protein (APP) co-segregates with FAD with perfect penetration, and the clinicopathological characteristics of patients with this mutation resemble that of sporadic AD. To examine the pathogenic process of this FAD-linked trait in vivo, we produced a mouse with the corresponding point mutation in the APP gene using homologous recombination and Cre-loxP site-specific recombination ('knock-in' technique). Mice with the heterozygous V642I-APP allele most precisely reflected the genotype of humans bearing this mutation. For the observation period of 2.5 years the mutants stayed apparently indistinguishable from the wild-type littermates. However, behavioural analysis revealed significantly deteriorated long-term memory in mutants when examined for the retention of spatial attention. Interestingly, acquisition of spatial memory was slightly affected but short-term working memory was not deteriorated at all. Histological examination was negative for formation of neuritic plaques or neurofibrillary tangles, whereas the relative amount of longer form of beta-amyloid species Abeta42(43) was significantly increased against that of the shorter form (Abeta40) in the mutant brain homogenates. We conclude that a V642I-APP mutant allele in aged mice confers functional components, but not organic components, of the AD-related phenotype that are observed in the early stage of AD. This V642I-APP knock-in mutant line may serve as a model to study the early pathogenic processes of AD in vivo and to develop therapeutics for this stage.