Biochemical and morphological characterization of the AβPP/PS/tau triple transgenic mouse model and its relevance to sporadic Alzheimer's disease.
Biochemical and morphological characterization of the AβPP/PS/tau triple transgenic mouse model and its relevance to sporadic Alzheimer's disease.
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DOI：
10.3233/jad-2011-110608
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Roher AE
中科院分区：
文献类型：
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作者：
Hunter JM;Bowers WJ;Maarouf CL;Mastrangelo MA;Daugs ID;Kokjohn TA;Kalback WM;Luehrs DC;Valla J;Beach TG;Roher AE
转基因（Tg）阿尔茨海默病（AD）小鼠模型已经被人类家族AD基因在强大的启动子驱动下进行了基因改造。然而，Tg模型必须准确地反映人类疾病的发病机制，而不仅仅是标志性的淀粉样蛋白和/或tau病理，因为这些特征可以通过多种趋同甚至与人类散发性阿尔茨海默病无关的致病机制产生。3×Tg-AD小鼠同时表达3种罕见的家族突变基因，这些基因在人类中独立产生破坏性的淀粉样蛋白-β前体（a -β pp）、早老素-1和额颞叶痴呆；因此，从技术上讲，这些小鼠不是散发性AD的模型，但在评估共同进化的淀粉样蛋白和tau病理方面提供了信息。虽然3×Tg-AD小鼠的终末期淀粉样蛋白和tau病变与散发性AD中观察到的相似，但导致这些病变的病理生理机制却截然不同。综合生化和形态学表征是衡量Tg小鼠预测价值的重要依据。对3×Tg-AD模型中Aβ - pp、淀粉样蛋白-β (Aβ)和tau蛋白的研究表明，与人类散发性AD相比，AD样病理存在一些关键差异。对a - β pp进行生化解剖，发现a - β pp c端与人AD的裂解模式不同，提示其致病机制存在差异。人类tau蛋白与a - β pp / a - β在幼年时同时表达，而大量的细胞外淀粉样蛋白斑块和成对的螺旋细丝在18个月后出现。通过严格的生化、病理和功能分析，了解Tg小鼠AD模型的优势和局限性，将有助于推导出更接近人类散发性AD的模型。
Transgenic (Tg) mouse models of Alzheimer’s disease (AD) have been genetically altered with human familial AD genes driven by powerful promoters. However, a Tg model must accurately mirror the pathogenesis of the human disease, not merely the signature amyloid and/or tau pathology, as such hallmarks can arise via multiple convergent or even by pathogenic mechanisms unrelated to human sporadic AD. The 3×Tg-AD mouse simultaneously expresses 3 rare familial mutant genes that in humans independently produce devastating amyloid-β protein precursor (AβPP), presenilin-1, and frontotemporal dementias; hence, technically speaking, these mice are not a model of sporadic AD, but are informative in assessing co-evolving amyloid and tau pathologies. While end-stage amyloid and tau pathologies in 3×Tg-AD mice are similar to those observed in sporadic AD, the pathophysiological mechanisms leading to these lesions are quite different. Comprehensive biochemical and morphological characterizations are important to gauge the predictive value of Tg mice. Investigation of AβPP, amyloid-β (Aβ), and tau in the 3×Tg-AD model demonstrates AD-like pathology with some key differences compared to human sporadic AD. The biochemical dissection of AβPP reveals different cleavage patterns of the C-terminus of AβPP when compared to human AD, suggesting divergent pathogenic mechanisms. Human tau is concomitantly expressed with AβPP/Aβ from an early age while abundant extracellular amyloid plaques and paired helical filaments are manifested from 18 months on. Understanding the strengths and limitations of Tg mouse AD models through rigorous biochemical, pathological, and functional analyses will facilitate the derivation of models that better approximate human sporadic AD.