Oddo Salvatore, Caccamo Antonella, Kitazawa Masashi, Tseng Bertrand P, LaFerla Frank M
Department of Neurobiology and Behavior, University of California, 1109 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4545, USA.
Neurobiol Aging. 2003 Dec;24(8):1063-70. doi: 10.1016/j.neurobiolaging.2003.08.012.
Amyloid-beta (Abeta) containing plaques and tau-laden neurofibrillary tangles are the defining neuropathological features of Alzheimer's disease (AD). To better mimic this neuropathology, we generated a novel triple transgenic model of AD (3xTg-AD) harboring three mutant genes: beta-amyloid precursor protein (betaAPPSwe), presenilin-1 (PS1M146V), and tauP301L. The 3xTg-AD mice progressively develop Abeta and tau pathology, with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We find that Abeta deposits initiate in the cortex and progress to the hippocampus with aging, whereas tau pathology is first apparent in the hippocampus and then progresses to the cortex. Despite equivalent overexpression of the human betaAPP and human tau transgenes, Abeta deposition develops prior to the tangle pathology, consistent with the amyloid cascade hypothesis. As these 3xTg-AD mice phenocopy critical aspects of AD neuropathology, this model will be useful in pre-clinical intervention trials, particularly because the efficacy of anti-AD compounds in mitigating the neurodegenerative effects mediated by both signature lesions can be evaluated.
含有β-淀粉样蛋白（Aβ）的斑块和富含tau蛋白的神经原纤维缠结是阿尔茨海默病（AD）的典型神经病理学特征。为了更好地模拟这种神经病理学，我们构建了一种新型的AD三重转基因模型（3xTg-AD），该模型携带三个突变基因：β-淀粉样前体蛋白（βAPP Swe）、早老素-1（PS1 M146V）和tau P301L。3xTg-AD小鼠逐渐出现Aβ和tau病理学变化，其时间和区域特异性特征与人类AD大脑中的发展情况极为相似。我们发现，随着年龄增长，Aβ沉积物始于皮质并发展至海马体，而tau病理学变化首先在海马体中显现，随后发展至皮质。尽管人类βAPP和人类tau转基因的过表达程度相同，但Aβ沉积先于缠结病理学出现，这与淀粉样蛋白级联假说一致。由于这些3xTg-AD小鼠模拟了AD神经病理学的关键方面，该模型将有助于临床前干预试验，特别是因为可以评估抗AD化合物减轻由这两种标志性病变介导的神经退行性作用的疗效。
