Amyloid deposition and advanced age fails to induce Alzheimer's type progression in a double knock-in mouse model.
Amyloid deposition and advanced age fails to induce Alzheimer's type progression in a double knock-in mouse model.
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发表时间：
2012-02
影响因子：
7.4
通讯作者：
Gauri H. Malthankar-Phatak;Yin-Guo Lin;N. Giovannone;R. Siman
中科院分区：
文献类型：
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作者：
Gauri H. Malthankar-Phatak;Yin-Guo Lin;N. Giovannone;R. Siman
开发能够再现阿尔茨海默病（AD）所有神经病理学特征的转基因和基因靶向小鼠模型一直具有挑战性。例如，在APP/PS-1双敲入突变小鼠（DKI）中，在中年时未观察到明显的神经变性，并且仅在淀粉样蛋白斑块内明显存在突触丧失。在这里，我们研究了持续的淀粉样蛋白沉积和24-27个月的高龄是否会导致神经元和突触的丢失，tau蛋白过度磷酸化以及AD的其他病理特征。我们专注于从内嗅皮层到海马齿状回的穿通通路投射，因为它在AD的早期过程中优先受到斑块、缠结和神经元损失的影响。与年龄和性别相匹配的野生型对照组相比，在起源的内嗅层2神经元中，reelin和NeuN的表达均未改变。荧光金逆行标记的穿支通路表明没有细胞丢失，轴突萎缩，或神经末梢变性。通过腹侧齿状回的体积分析和突触标记物的免疫染色证实了神经元损失或萎缩的缺乏。我们还通过标记过度磷酸化的前缠结tau蛋白、含组织蛋白酶D的自溶酶体的积累和细胞周期蛋白A阳性神经元异常地重新进入细胞周期来寻找AD神经病理学的其他标志。在内嗅皮层、齿状回或任何其他前脑区域均未观察到这些AD病理。我们的研究结果表明，DKI小鼠没有表现出明显的阿尔茨海默型疾病进展，即使在高龄和超过18个月的强大的大脑淀粉样蛋白沉积的阶段。淀粉样蛋白沉积不足以诱导衰老小鼠脑中的其他AD型神经病理学和神经变性，表明tau蛋白病或其他因素在触发AD发病机制中的重要作用。
It has been challenging to develop transgenic and gene-targeted mouse models that recapitulate all of the neuropathological features of Alzheimer's disease (AD). For example, in the APP/PS-1 double knock-in mutant mouse (DKI), frank neurodegeneration is not observed at middle age and synapse loss is pronounced only within amyloid plaques. Here, we investigated whether continued amyloid deposition and advanced age of 24-27 months lead to loss of neurons and synapses, tau hyperphosphorylation, and other pathological features of AD. We focused on the perforant pathway projection from entorhinal cortex to hippocampal dentate gyrus, since it is preferentially impacted by plaques, tangles, and neuronal loss early in the course of AD. Compared with wild type controls matched for age and gender, expression of neither reelin nor NeuN was altered in the entorhinal layer 2 neurons of origin. Retrograde labeling of the perforant pathway with Fluorogold indicated no cell loss, axonal atrophy, or nerve terminal degeneration. The lack of neuronal loss or atrophy was confirmed by volumetric analysis of the ventral dentate gyrus and immunostaining for a synaptic marker. We also searched for other hallmarks of AD neuropathology by labeling for hyperphosphorylated pre-tangle tau, accumulation of cathepsin D-containing autolysosomes, and cyclin A-positive neurons aberrantly re-entering the cell cycle. None of these AD pathologies were observed in the entorhinal cortex, dentate gyrus, or any other forebrain region. Our results indicate that the DKI mouse does not show appreciable Alzheimer-type disease progression, even at advanced age and in the phase of over 18 months of robust cerebral amyloid deposition. The insufficiency of amyloid deposition to induce other AD-type neuropathologies and neurodegeneration in the aging mouse brain suggests an important role for tauopathy or other factors for triggering the pathogenesis of AD.