A transgenic rat that develops Alzheimer's disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment
A transgenic rat that develops Alzheimer's disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment
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DOI：
10.1016/j.nbd.2008.03.005
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发表时间：
2008-07-01
影响因子：
6.1
通讯作者：
Duff, Karen
中科院分区：
文献类型：
--
作者：
Liu, Li;Orozco, Ian J.;Duff, Karen
在过去的十年中，已经创建了多个转基因APP过表达小鼠品系，其重现了阿尔茨海默病（AD）的某些方面。然而，先前报道的转基因APP过表达大鼠模型均未出现AD样β淀粉样蛋白（A β）沉积或年龄相关的学习和记忆缺陷。在本研究中，我们表征了过表达具有三种家族性AD突变（两种在APP中，一种在PS1中）的转基因的转基因大鼠模型，所述突变由Flood等人[Flood，D.G.，例如，阿尔茨海默病转基因大鼠模型中的β沉积。神经科学学会2003，华盛顿，DC，2003]。从9个月大开始，这些大鼠出现弥漫性和致密形式的A β沉积，后者与活化的小胶质细胞和反应性星形胶质细胞密切相关。在7个月大的大鼠海马切片上进行的电生理记录显示了受损的长时程增强（UP），这是淀粉样斑块出现前2个月。LTP的缺陷伴随着莫里斯水迷宫中的空间学习和记忆受损，这在13个月大的转基因大鼠中变得更加明显。对于两个年龄段的Tg大鼠，认知障碍有与海马中总A β 42水平相关的趋势。因此，大鼠模型概括了AD样淀粉样蛋白病理学和认知障碍。大鼠模型相对于现有小鼠模型的优势在于，大鼠为高级研究提供了更好的机会，例如连续CSF采样、电生理学、神经成像、基于细胞的移植操作和复杂的行为测试。(C)2008年爱思唯尔公司All rights reserved.
In the last decade, multiple lines of transgenic APP overexpressing mice have been created that recapitulate certain aspects of Alzheimer's disease (AD). However, none of the previously reported transgenic APP overexpressing rat models developed AD-like beta-amyloid (A beta) deposits, or age-related learning and memory deficits. In the present study, we have characterized a transgenic rat model overexpressing transgenes with three, familial AD mutations (two in APP and one in PS1) that were developed by Flood et al. [Flood, D.G., et al., A beta deposition in a transgenic rat model of Alzheimer's disease. Society for Neuroscience 2003, Washington, DC, 2003]. From the age of 9 months, these rats develop A beta deposits in both diffuse and compact forms, with the latter being closely associated with activated microglia and reactive astrocytes. Impaired long-term potentiation (UP) was revealed by electropbysiological recordings performed on hippocampal slices from rats at 7 months of age, which is 2 months before the appearance of amyloid plaques. The deficit in LTP was accompanied by impaired spatial learning and memory in the Morris water maze, which became more pronounced in transgenic rats of 13 months of age. For Tg rats of both ages, there was a trend for cognitive impairment to correlate with total A beta 42 levels in the hippocampus. The rat model therefore recapitulates AD-like amyloid pathology and cognitive impairment. The advantage of the rat model over the available mouse models is that rats provide better opportunities for advanced studies, such as serial CSF sampling, electrophysiology, neuroimaging, cell-based transplant manipulations, and complex behavioral testing. (C) 2008 Elsevier Inc. All rights reserved.