Massive CA1/2 neuronal loss with intraneuronal and N-interminal truncated Aβ42 accumulation in a novel Alzheimer transgenic model
Massive CA1/2 neuronal loss with intraneuronal and N-interminal truncated Aβ42 accumulation in a novel Alzheimer transgenic model
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DOI：
10.1016/s0002-9440(10)63388-3
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发表时间：
2004-10-01
影响因子：
6
通讯作者：
Pradier, L
中科院分区：
文献类型：
--
作者：
Casas, C;Sergeant, N;Pradier, L
阿尔茨海默病（AD）的特点是锥体神经元的实质性变性和神经斑块和神经原纤维缠结的出现。在这里，我们提出了一种新的转基因小鼠模型APP(SL)PS1KI，它密切模仿ad相关神经病理特征的发展，包括显著的海马神经元损失。该转基因小鼠模型携带早老素-1中M233T/L235P敲入突变，并过度表达突变的人β -淀粉样蛋白（Abeta）前体蛋白。Abeta（x-42）是该模型中存在的Abeta物种的主要形式，随着n -截断变体和二聚体的复杂模式的逐渐发展，类似于在AD大脑中观察到的情况。在10月龄时，CA1/2海马锥体细胞层存在广泛的神经元损失（约50%），这与神经元内Abeta和硫黄素- s阳性细胞内物质的强烈积累有关，但与细胞外Abeta沉积无关。强烈的反应性星形胶质细胞增生伴随着神经元的丧失而发展。这种损失在6个月大时就可以检测到，并且与PS1KI基因的剂量有关。因此，APP(SL)PS1KI小鼠进一步证实了神经元内Abeta（42）在神经元丢失中的关键作用，并为研究旨在预防AD神经退行性变的治疗策略提供了一个很好的工具。
Alzheimer's disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APP(SL)PS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human beta-amyloid (Abeta) precursor protein. Abeta(x-42) is the major form of Abeta species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain. At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Abeta and thioflavine-S-positive intracellular material but not with extracellular Abeta deposits. A strong reactive astrogliosis develops together with the neuronal loss. This loss is already detectable at 6 months of age and is PS1KI gene dosage-dependent. Thus, APP(SL)PS1KI mice further confirm the critical role of intraneuronal Abeta(42) in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.