Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
PLoS One. 2012;7(12):e51432. doi: 10.1371/journal.pone.0051432. Epub 2012 Dec 7.
Alzheimer's disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and may result from multiple etiologic factors, including environmental, genetic and metabolic factors, whereas FAD is caused by mutations of presenilins or amyloid-β (Aβ) precursor protein (APP). A commonly used mouse model for AD is 3xTg-AD mouse, which is generated by over-expression of mutated presenilin 1, APP and tau in the brain and thus represents a mouse model of FAD. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), icv-STZ mouse, shows many aspects of SAD. Despite the wide use of these two models for AD research, differences in gene expression between them are not known. Here, we compared the expression of 84 AD-related genes in the hippocampus and the cerebral cortex between icv-STZ mice and 3xTg-AD mice using a custom-designed qPCR array. These genes are involved in APP processing, tau/cytoskeleton, synapse function, apoptosis and autophagy, AD-related protein kinases, glucose metabolism, insulin signaling, and mTOR pathway. We found altered expression of around 20 genes in both mouse models, which affected each of above categories. Many of these gene alterations were consistent with what was observed in AD brain previously. The expression of most of these altered genes was decreased or tended to be decreased in the hippocampus of both mouse models. Significant diversity in gene expression was found in the cerebral cortex between these two AD mouse models. More genes related to synaptic function were dysregulated in the 3xTg-AD mice, whereas more genes related to insulin signaling and glucose metabolism were down-regulated in the icv-STZ mice. The present study provides important fundamental knowledge of these two AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.
阿尔茨海默病（AD）可分为散发性 AD（SAD）和家族性 AD（FAD）。大多数 AD 病例为散发性，可能由多种病因因素引起，包括环境、遗传和代谢因素，而 FAD 是由早老素或淀粉样β（Aβ）前体蛋白（APP）突变引起的。AD 的一种常用小鼠模型是 3xTg-AD 小鼠，它是通过在大脑中过度表达突变的早老素 1、APP 和 tau 而产生的，因此代表了 FAD 的小鼠模型。通过脑室内（icv）给予链脲佐菌素（STZ）产生的 AD 小鼠模型 icv-STZ 小鼠，表现出许多 SAD 方面的特征。尽管这两种模型被广泛用于 AD 研究，但它们之间的基因表达差异尚不清楚。在这里，我们使用定制设计的 qPCR 阵列比较了 icv-STZ 小鼠和 3xTg-AD 小鼠海马体和大脑皮层中 84 种与 AD 相关的基因的表达。这些基因参与 APP 加工、tau/细胞骨架、突触功能、细胞凋亡和自噬、AD 相关蛋白激酶、葡萄糖代谢、胰岛素信号和 mTOR 通路。我们发现这两种小鼠模型中大约有 20 个基因的表达发生了改变，这些改变影响了上述每一类。这些基因改变中的许多与之前在 AD 大脑中观察到的一致。这两种小鼠模型的海马体中，大多数这些改变基因的表达降低或趋于降低。这两种 AD 小鼠模型之间大脑皮层中的基因表达存在显著差异。在 3xTg-AD 小鼠中，更多与突触功能相关的基因失调，而在 icv-STZ 小鼠中，更多与胰岛素信号和葡萄糖代谢相关的基因下调。本研究为这两种 AD 小鼠模型提供了重要的基础知识，并将有助于指导未来使用这两种小鼠模型进行 AD 药物开发的研究。
