Evotec Neurosciences GmbH, Hamburg, Germany.
PLoS One. 2009 Nov 20;4(11):e7931. doi: 10.1371/journal.pone.0007931.
Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral beta-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.
METHODOLOGY/PRINCIPAL FINDINGS: The transgenic mouse line (ARTE10) was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APP(swe)) and the M146V mutated presenilin 1 (PS1) both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral beta-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a gamma-secretase inhibitor we show a dose dependent reduction of soluble amyloid beta levels in the brain.
ARTE10 mice develop a cerebral beta-amyloidosis closely resembling the beta-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for the use in target validation and for evaluating potential diagnostic or therapeutic agents targeting the amyloid pathology of AD.
表达突变淀粉样前体蛋白（APP）和早老素（PS）-1 或 -2 的转基因小鼠已成功用于模拟阿尔茨海默病（AD）病理学的特征性标志之一——脑β-淀粉样蛋白沉积。然而，许多转基因系的使用受到以下因素的限制：过早死亡、繁殖效率低、病理学发病晚且个体间差异大，因此需要改进动物模型。本文详细描述了一种新的纯合双转基因小鼠系的特征，该模型解决了上述大部分问题。
方法/主要发现：该转基因小鼠系（ARTE10）通过共整合两个携带 K670N/M671L 突变淀粉样前体蛋白（APP(swe)）和 M146V 突变早老素 1（PS1）的转基因而产生，这两个基因均受神经元特异性启动子的控制。半合子和纯合子的转基因小鼠都是可育和有繁殖能力的，并且具有较低的早亡率。它们会出现典型的 AD 样脑β-淀粉样斑块病理学，伴有神经胶质炎症、神经突营养不良和脑淀粉样血管病的迹象。使用我们新的半自动化斑块负荷定量分析算法，我们证明了在纯合子小鼠中，从 3 个月大开始就出现了早发性和进行性斑块沉积，个体间变异性低，表型的出现率为 100%。斑块可以通过 PiB（AD 的标准人类 PET 示踪剂）在体内被轻易检测到。此外，ARTE10 小鼠还表现出早期突触标志物丢失和与年龄相关的认知缺陷。通过应用γ-分泌酶抑制剂，我们发现大脑中可溶性淀粉样β水平呈剂量依赖性降低。
ARTE10 小鼠会发展出一种与人类 AD 神经病理学中β-淀粉样蛋白相关的脑β-淀粉样蛋白沉积。该模型结合了之前转基因模型的几个优点，特别适合用于目标验证和评估针对 AD 淀粉样蛋白病理的潜在诊断或治疗药物。
