Department of Neurobiology, Care Sciences and Society, Karolinska Institutet Alzheimer Disease Research Center, Karolinska Institutet, Huddinge, Sweden.
Neurobiol Aging. 2012 Apr;33(4):831.e11-9. doi: 10.1016/j.neurobiolaging.2011.07.012. Epub 2011 Aug 31.
The Arctic APP mutation (E693G) within the amyloid β (Aβ) domain of amyloid precursor protein (APP) leads to dementia with clinical features similar to Alzheimer's disease (AD), which is believed to be mediated via increased formation of protofibrils. We have generated a transgenic mouse model, TgAPParc, with neuron-specific expression of human amyloid precursor protein with the Arctic mutation (hAPParc), showing mild amyloid pathology with a relatively late onset. Here we performed a detailed analysis of the spatiotemporal progression of neuropathology in homozygous TgAPParc, focusing on intracellular Aβ and diffuse Aβ aggregates rather than amyloid plaques. We show that the neuropathology in homozygous TgAPParc mice starts with intracellular Aβ aggregates, which is followed by diffuse extracellular Aβ deposits in subiculum that later expands to brain regions receiving neuronal projections from regions already affected. Together this suggests that the pathology in TgAPParc mice affects interconnected brain regions and may represent a valuable tool to study the spread and progression of neuropathology in Alzheimer's disease.
淀粉样前体蛋白（APP）中的北极 APP 突变（E693G）位于淀粉样蛋白 β（Aβ）结构域内，导致具有类似于阿尔茨海默病（AD）临床特征的痴呆症，据信这是通过原纤维形成增加介导的。我们生成了一种具有神经元特异性表达人类淀粉样前体蛋白北极突变体（hAPParc）的转基因小鼠模型 TgAPParc，其表现出轻度淀粉样病理学，发病较晚。在这里，我们对同种型 TgAPParc 的神经病理学进行了详细分析，重点关注细胞内 Aβ 和弥散性 Aβ 聚集体，而不是淀粉样斑块。我们发现，同种型 TgAPParc 小鼠的神经病理学始于细胞内 Aβ 聚集体，随后在 subiculum 中出现弥散性细胞外 Aβ 沉积，随后扩展到已经受到影响的区域向其投射神经元的脑区。总的来说，这表明 TgAPParc 小鼠的病理学影响了相互连接的脑区，可能是研究阿尔茨海默病神经病理学传播和进展的有价值工具。
